Materiały źródłowe

• #1 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Lynch syndrome is the familial clustering of colorectal and endometrial cancers. This syndrome is passed in an autosomal dominant fashion within families with defective mismatch repair as the genetic basis for cancer development in these patients. […] Identification of alternate genetic mutations such as EPCAM and CHEK2 may explain the cancer risk in a small subset of these patients, but continuing work into the genetic basis of colorectal familial cancer syndromes is needed. […] Lynch syndrome is an autosomally dominant inherited genetic disease. Microsatellite instability (MSI) is the hallmark of tumors in Lynch syndrome patients. […] Tumors that have microsatellite instability develop in Lynch syndrome patients due to inheritance of a germline mutation in DNA mismatch repair mechanisms.

• #2 Recent advances in Lynch syndrome | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00231-4

  Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. […] The function of DNA MMR is to maintain genomic stability, and the dysfunction of DNA MMR could lead to alterations in the repetitive sequence number of microsatellites, which is defined as microsatellite instability (MSI). […] Commonly, high frequency of MSI (MSI-H) is shown in tumors developed in LS individuals with variants in MMR genes. […] The cumulative cancer incidences of MLH1, MSH2, MSH6, or PMS2 variant carriers up to age 75 are as follows: MLH1: 81% (females), 71.4% (males); MSH2: 84.3% (females), 75.2% (males); MSH6: 61.8% (females), 41.7% (males); and PMS2: 34.1% (both sexes). […] A study showed that a significant proportion of patients with Bethesda criteria who have loss of MLH1 protein expression in their tumors and do not have an MLH1 pathogenic germline mutation display constitutional MLH1 methylation as the mechanism of Lynch syndrome. […] EPCAM deletion usually rarely causes extragastrointestinal tumors. […] Studies have reported that although PMS2 pathogenic variant carriers may not increase the tumorigenesis of CRC, the lack of PMS2 protein can promote the progression of MMR mature adenoma to CRC.

• #3 Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis – UpToDate

  https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis

  Lynch syndrome is the most common cause of inherited colorectal cancer (CRC). It is characterized by a significantly increased risk for CRC and endometrial cancer as well as a risk of several other malignancies. […] Lynch syndrome refers to patients and families with a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene. […] Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes or loss of expression of MSH2 due to deletion in the EPCAM gene (previously called TACSTD1). The MMR genes that are associated with Lynch syndrome include:

• #4 SciELO Brazil – Mismatch repair genes in Lynch syndrome: a review Mismatch repair genes in Lynch syndrome: a review

  https://www.scielo.br/j/spmj/a/KHmVWSq53tmSx6n3jznsB8n/

  Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. […] Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). […] It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. […] Much progress has been made in understanding the molecular basis of Lynch Syndrome.

• #5 Lynch Syndrome AHS – M2004 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/lynch-syndrome

  Lynch syndrome (LS) (also known as hereditary non-polyposis colorectal cancer; HNPCC) is the most common form of hereditary colorectal (CRC) and endometrial cancers (EMC), resulting from an autosomal dominant inactivation of any of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) leading to microsatellite instability (MSI) (Rumilla et al., 2011) and associated with an increased risk of colorectal, endometrial, stomach, small bowel, and ovarian cancers (Hunter et al., 2015; Lynch et al., 2009; Moreira et al., 2012). […] Lynch syndrome (LS) is recognized by a hereditary predisposition to colorectal, endometrial, and other cancers due to inactivation by germline mutations or epigenetic silencing in any of the four DNA mismatch repair genes- MLH1, MSH2, MSH6, and PMS2. Mutations in MLH1 and MSH2 are most common (90%) followed by MSH6 (10%) and PMS2 (6%) (Jansen et al., 2014).

• #6 Lynch syndrome in a nutshell – Lynsight

  https://lynsightlabs.com/lynch-syndrome-in-a-nutshell/

  Lynch syndrome is the most prevalent hereditary cancer syndrome, with an estimated prevalence of 1 in 279, which would globally translate to 30 million people. […] LS predisposes the affected persons to cancers, especially to colorectal cancer (CRC) and endometrial cancer (EC), because of an inherited defect in the DNA mismatch repair (MMR) mechanism. […] Lynch Syndrome associated cancer develops because of malfunction in the DNA mismatch repair (MMR). […] Typically, the MMR mechanism corrects errors that arise during DNA replication and recombination, and maintains genomic stability in a cell. A functional MMR produces repair proteins, transports them to the nucleus, and forms protein complexes that perform the actual repair. In Lynch syndrome, an inherited gene alteration disrupts this function and predisposes to cancer.

• #7 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Lynch syndrome is the familial clustering of colorectal and endometrial cancers. This syndrome is passed in an autosomal dominant fashion within families with defective mismatch repair as the genetic basis for cancer development in these patients. […] Identification of alternate genetic mutations such as EPCAM and CHEK2 may explain the cancer risk in a small subset of these patients, but continuing work into the genetic basis of colorectal familial cancer syndromes is needed. […] Lynch syndrome is an autosomally dominant inherited genetic disease. Microsatellite instability (MSI) is the hallmark of tumors in Lynch syndrome patients. […] Tumors that have microsatellite instability develop in Lynch syndrome patients due to inheritance of a germline mutation in DNA mismatch repair mechanisms.

• #8 Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431096/

  Lynch syndrome results from a germline mutation in 1 of 4 mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. […] Mismatch repair genes are necessary for correcting incorrect pairing of nucleotide bases during DNA replication. If these mismatches are not resolved, the resulting copy may not function properly, leading to an increased cancer risk. These mutations lead to a high amount of microsatellite instability (MSI). […] Lynch syndrome is due to autosomal dominant germline mutations in genes involved in DNA mismatch repair. Mutations of these genes lead to frameshift alterations and, ultimately, to accumulating these errors within microsatellites. Microsatellites are nucleotide repeats which, when functional, are identical in every cell within 1 person. Mutations in mismatch repair allow for the proliferation of aberrant microsatellites within tumor suppressor genes, resulting in cancerous growth.

• #9 Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis – UpToDate

  https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis

  Lynch syndrome is the most common cause of inherited colorectal cancer (CRC). It is characterized by a significantly increased risk for CRC and endometrial cancer as well as a risk of several other malignancies. […] Lynch syndrome refers to patients and families with a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene. […] Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes or loss of expression of MSH2 due to deletion in the EPCAM gene (previously called TACSTD1). The MMR genes that are associated with Lynch syndrome include:

• #10 Recent advances in Lynch syndrome | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00231-4

  Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. […] The function of DNA MMR is to maintain genomic stability, and the dysfunction of DNA MMR could lead to alterations in the repetitive sequence number of microsatellites, which is defined as microsatellite instability (MSI). […] Commonly, high frequency of MSI (MSI-H) is shown in tumors developed in LS individuals with variants in MMR genes. […] The cumulative cancer incidences of MLH1, MSH2, MSH6, or PMS2 variant carriers up to age 75 are as follows: MLH1: 81% (females), 71.4% (males); MSH2: 84.3% (females), 75.2% (males); MSH6: 61.8% (females), 41.7% (males); and PMS2: 34.1% (both sexes). […] A study showed that a significant proportion of patients with Bethesda criteria who have loss of MLH1 protein expression in their tumors and do not have an MLH1 pathogenic germline mutation display constitutional MLH1 methylation as the mechanism of Lynch syndrome. […] EPCAM deletion usually rarely causes extragastrointestinal tumors. […] Studies have reported that although PMS2 pathogenic variant carriers may not increase the tumorigenesis of CRC, the lack of PMS2 protein can promote the progression of MMR mature adenoma to CRC.

• #11 Lynch syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/lynch-syndrome/

  Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer. […] Variants that cause a disease or increase the risk for a disease are sometimes called pathogenic variants. Pathogenic variants in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes can cause Lynch syndrome. […] The MLH1, MSH2, MSH6, and PMS2 genes are involved in repairing the errors that occur when DNA is copied in preparation for cell division, a process called DNA replication. Because these genes work together to fix DNA errors, they are known as mismatch repair (MMR) genes. Pathogenic variants in any of these MMR genes can cause Lynch syndrome. […] Changes in the EPCAM gene can also disrupt DNA repair, although the gene itself is not directly involved in this process. The EPCAM gene lies next to the MSH2 gene on chromosome 2, and certain EPCAM gene variants cause the MSH2 gene to be turned off (inactivated). As a result, the MSH2 gene’s role in DNA repair is disrupted, which can lead to accumulated DNA errors and cancer development.

• #12 SciELO Brasil – Mismatch repair genes in Lynch syndrome: a review Mismatch repair genes in Lynch syndrome: a review

  https://www.scielo.br/j/spmj/a/KHmVWSq53tmSx6n3jznsB8n/?lang=en

  Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens. […] Lynch syndrome is characterized by an accelerated process of carcinogenesis due to mismatch repair gene mutations. […] The major genes involved are mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), postmeiotic segregation increased 2 (PMS2), mutS homolog 6 (MSH6) and mutL homolog 3 (MLH3). […] Germline abnormalities in MLH1 and MSH2 genes are found in more than 90% of HNPCC mutation carriers. […] According to Papp et al., there are more than 500 different pathogenic mutations: 50% relating to MLH1, 40% to MSH2 and 10% distributed among the others.

• #13 Lynch Syndrome (HNPCC) Causes | Stanford Health Care

  https://stanfordhealthcare.org/medical-conditions/cancer/lynch-syndrome/hnpcc-causes.html

  The majority of HNPCC cases are caused by mutations in one of several mismatch-repair genes: MSH2, MSH6, and PMS1 on chromosome 2, MLH1 on chromosome 3, MSH3 on chromosome 5, and PMS2 on chromosome 7. MLH1 and MSH2 are the genes most commonly implicated. Mutations in any one of these genes confers an increased lifetime risk to develop colorectal cancer and, in females, an increased risk to develop ovarian (12%) and endometrial (up to 60%) cancer. The genes responsible for HNPCC are mismatch-repair genes, which correct „spelling errors” in DNA that happen during the cell division process. When these genes are altered, or mutated, however, mismatches in the DNA remain. If mismatches accumulate in cell growth control genes, like proto-oncogenes and tumor suppressor genes, this will eventually lead to uncontrolled cell growth and tumor formation. Both copies of a mismatch-repair gene must be altered, or mutated, before a person will develop cancer.

• #14 SciELO Brasil – Mismatch repair genes in Lynch syndrome: a review Mismatch repair genes in Lynch syndrome: a review

  https://www.scielo.br/j/spmj/a/KHmVWSq53tmSx6n3jznsB8n/?lang=en

  Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens. […] Lynch syndrome is characterized by an accelerated process of carcinogenesis due to mismatch repair gene mutations. […] The major genes involved are mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), postmeiotic segregation increased 2 (PMS2), mutS homolog 6 (MSH6) and mutL homolog 3 (MLH3). […] Germline abnormalities in MLH1 and MSH2 genes are found in more than 90% of HNPCC mutation carriers. […] According to Papp et al., there are more than 500 different pathogenic mutations: 50% relating to MLH1, 40% to MSH2 and 10% distributed among the others.

• #15 Lynch Syndrome AHS – M2004 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/lynch-syndrome

  Lynch syndrome (LS) (also known as hereditary non-polyposis colorectal cancer; HNPCC) is the most common form of hereditary colorectal (CRC) and endometrial cancers (EMC), resulting from an autosomal dominant inactivation of any of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) leading to microsatellite instability (MSI) (Rumilla et al., 2011) and associated with an increased risk of colorectal, endometrial, stomach, small bowel, and ovarian cancers (Hunter et al., 2015; Lynch et al., 2009; Moreira et al., 2012). […] Lynch syndrome (LS) is recognized by a hereditary predisposition to colorectal, endometrial, and other cancers due to inactivation by germline mutations or epigenetic silencing in any of the four DNA mismatch repair genes- MLH1, MSH2, MSH6, and PMS2. Mutations in MLH1 and MSH2 are most common (90%) followed by MSH6 (10%) and PMS2 (6%) (Jansen et al., 2014).

• #16 An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms | OMICS International

  https://www.omicsonline.org/an-update-on-the-pathogenesis-of-lynch-syndrome-recently-described-novel-molecular-mechanisms-2161-069X-3-151.php?aid=21289

  Recently, several novel genetic abnormalities have been identified which lead to the Lynch syndrome phenotype and may explain differences in the rates and risk of extracolonic malignancies. […] Among these novel mechanisms, EPCAM deletions, CHEK2 mutations, and germline promoter hypermethylation of MLH1 have been described with evidence that these are responsible for some of the MMR-negative cases.

• #17 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  When MMR genes become mutated, several specific genes contain microsatellites in their coding region and become susceptible to the accumulation of mutations. […] The key differentiating factor is that sporadic cancers are the result of somatic hypermethylation rather than germ-line hypermethylation. […] Historically, the underlying mechanism for Lynch syndrome is the result of an autosomal dominant DNA mismatch repair [MMR] deficiency with resultant tumor microsatellite instability [MSI]. […] Current data suggests that 10 to 40% of the patients with early-onset colorectal cancer (mean age 43), and malignancies involving the duodenum, ileum, appendix, endometrium, and bladder may have an EPCAM mutation. […] Another intriguing mechanism for Lynch syndrome is the germ-line promoter hypermethylation of MLH1. […] The exact phenotype, tumor spectrum, and incidence remain to be defined for germ-line hypermethylation.

• #18 Significance of rare variants in genes involved in the pathogenesis of Lynch syndrome

  https://www.spandidos-publications.com/10.3892/ijmm.2022.5137

  The present study also suggested analyzing other MMR genes, such as MLH3, in panels used for the molecular screening of LS. […] The study of hereditary forms of CRC has increased the importance of genetic testing. […] The remaining pathogenic variants were identified in MMR genes (MLH1 and MSH6) in patients who met the AC and showed a typical LS phenotype with MSI-H status in cancer tissues. […] The results herein revealed that the use of the custom panel allowed the identification of variants in genes not routinely analyzed for cases with a clinical suspicion of LS, mainly variants in the MLH3 gene, but also rare variants identified in genes such as CHEK2, ATM, MSH3 and NF1. […] The assessment of rare uncertain variants in genetic counseling could improve the risk estimate in those families that remain without a clear molecular diagnosis to provide precision medicine for this pathogenic condition.

• #19 An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms | OMICS International

  https://www.omicsonline.org/an-update-on-the-pathogenesis-of-lynch-syndrome-recently-described-novel-molecular-mechanisms-2161-069X-3-151.php?aid=21289

  Lynch syndrome, originally described in 1913 and previously known as hereditary nonpolyposis colorectal carcinoma syndrome, is the most common hereditary cancer syndrome. This syndrome is classically due to germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. […] Recently, EPCAM deletion, CHEK2 mutations, and germline MLH1 hypermethylation have been identified as alternative mutations that cause Lynch syndrome in mismatch repair-negative patients. This article reviews these novel mechanisms and mutations, their clinical significance, and the pathogenesis of these Lynch causing mutations. […] A subset of approximately 40% of patients with Lynch syndrome that meet clinical criteria and have a microsatellite instability-high colorectal cancer do not have an identifiable mutation in one of the four mismatch repair genes.

• #20

  https://dokumen.pub/lynch-syndrome-molecular-mechanism-and-current-clinical-practice-1st-ed-9789811568909-9789811568916.html

  The inactivation of MSH2 leads to the inability to form MutS complexes and the concurrent loss of MSH2 and MSH6. […] The MMR pathway corrects single basebase or insertion/deletion (indel) mismatches resulted from misincorporation by DNA polymerases during DNA replication. […] The MMR pathway is one of the major DNA repair mechanisms which is conserved from prokaryotes to higher eukaryotes. […] Lynch syndrome is caused by germline pathogenic variants in the mismatch repair (MMR) genes. […] The MMR pathway corrects single basebase or insertion/deletion (indel) mismatches resulted from misincorporation by DNA polymerases during DNA replication. […] The spectrum of cancers observed in patients with CMMRD is apparently different from that found in LS. […] The MMR pathway is one of the major DNA repair mechanisms which is conserved from prokaryotes to higher eukaryotes.

• #21 Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK431096/

  Lynch syndrome results from a germline mutation in 1 of 4 mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. […] Mismatch repair genes are necessary for correcting incorrect pairing of nucleotide bases during DNA replication. If these mismatches are not resolved, the resulting copy may not function properly, leading to an increased cancer risk. These mutations lead to a high amount of microsatellite instability (MSI). […] Lynch syndrome is due to autosomal dominant germline mutations in genes involved in DNA mismatch repair. Mutations of these genes lead to frameshift alterations and, ultimately, to accumulating these errors within microsatellites. Microsatellites are nucleotide repeats which, when functional, are identical in every cell within 1 person. Mutations in mismatch repair allow for the proliferation of aberrant microsatellites within tumor suppressor genes, resulting in cancerous growth.

• #22

  https://dokumen.pub/lynch-syndrome-molecular-mechanism-and-current-clinical-practice-1st-ed-9789811568909-9789811568916.html

  Mismatch repair proteins are involved in repairing of incorrect pairing, including point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites, that can arise during DNA replication. […] Lynch syndrome develops in adulthood, but MMR gene abnormalities are observed in children with different genotypes and phenotypes. […] The phenotype indicating the mismatch repair deficiency can be frequently observed as a microsatellite instability (MSI) in tumors. […] Lynch syndrome is a state of mismatch repair deficiency (MMRd) due to a monoallelic abnormality of the mismatch repair genes. […] The mismatch repair system consists of sequential steps for the recognition, removal, and resynthesis of the mismatch site in DNA. […] The MMR proteins relevant to Lynch syndrome act as heterodimers.

• #23 Molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome)

  http://www.scielo.org.co/scielo.php?script=sci_arttext&pid=S0120-00112016000300537

  Lynch syndrome is the most common cause of inherited colorectal cancer, totaling 5 to 8% of all the cases with high susceptibility to this type of cancer and extracolonic cancer. It is related to germinal mutations taking place at mismatch repair genes. […] Lynch syndrome is the most common cause of inherited CRC and represents 5-8% of all cases; it is associated with mutations in the germline of MMR genes including hMLH1, hMSH2, hMSH6, hPMS2, hPMS1 and hMLH3, which generate microsatellite instability in most cases. About 90% of the mutations identified in this group correspond to hMLH1 (50%) and hMSH2 (40%) genes. […] The MMR has evolved to correct errors that are beyond 3′ 5′ exonuclease correction activity of DNA polymerases. The process begins with the recognition of the mismatch caused by the binding of the hMSH2/hMSH6 heterodimer, also known as hMutSa; this complex undergoes a conformational change promoted by ATP which turns it into a clamp, which is displaceable through the DNA strand and, then, recruits the hMLH1 / hPMS2 heterodimer, also known as hMuLa.

• #24 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The DNA MMR system provides recognition of post-DNA synthetic polymerase mistakes in the DNA strand at single base mispairs, chemotherapy-induced nucleotide alterations, and slippage mistakes at repetitive sequences termed microsatellites. […] Abrogation of DNA MMR function generates a hypermutated tumor that accumulates hundreds of random point mutations and frameshifts in the cells genome, and transition from an adenoma to CRC occurs at a rapid pace compared to MMR-intact tumors (1-3 years vs 1-2 decades, respectively). […] The biomarker assay that is used to determine loss of MMR function clinically is microsatellite instability (MSI), which detects acquired new frameshift length changes of microsatellites in neoplastic tissue compared to non-neoplastic tissue when MMR function is defective.

• #25 Urologic implications of Lynch syndrome

  https://www.urologytimes.com/view/urologic-implications-of-lynch-syndrome

  Lynch syndrome (LS) is one of the most common hereditary cancer disorders and includes multiple urologic cancers within its spectrum. This autosomal dominant syndrome was one of the first hereditary cancer disorders to be identified and affects approximately 1 in 279 people. LS is historically known as hereditary nonpolyposis colorectal cancer (HNPCC) but is also associated with urothelial, prostate, testicular, and adrenal malignancies. […] The carcinogenic mechanism of LS is caused by a mutation within the mismatch repair (MMR) genes, with the most common mutations being in the mutL homolog 1 (MLH1), mutS homolog 2 and 6 (MSH2, MSH6), and postmeiotic segregation increased 2 (PMS2). Mutations in the epithelial cellular adhesion molecule (EpCAM) can also lead to silencing of MSH2. MMR genes work together to identify and excise DNA mismatches during DNA synthesis, and mutation of a single protein in this pathway can lead to dysfunction of the entire repair system. The inherited germline mutation alone is not enough to lead to disruption of the MMR system. The second normal allele must be inactivated as well, typically through epigenetic silencing, somatic mutation, or loss of heterozygosity.

• #26

  https://link.springer.com/article/10.1007/s10689-013-9635-x

  The majority of Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), has been linked to heterozygous defects in DNA mismatch repair (MMR). […] Loss-of-heterozygosity (LOH) that retains the mutant MMR allele and epigenetic silencing of MMR genes are associated with an increased mutation rate that drives carcinogenesis as well as microsatellite instability that is a hallmark of LS/HNPCC. […] Understanding the biophysical functions of the MMR components is crucial to elucidating the role of MMR in human tumorigenesis and determining the pathogenetic consequences of patients that present in the clinic with an uncharacterized variant of the MMR genes. […] We summarize the historical association between LS/HNPCC and MMR, discuss the mechanism of the MMR and finally examine the functional analysis of MMR defects found in LS/HNPCC patients and their relationship with the severity of the disease.

• #27 Lynch Syndrome (HNPCC) Causes | Stanford Health Care

  https://stanfordhealthcare.org/medical-conditions/cancer/lynch-syndrome/hnpcc-causes.html

  With HNPCC, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. For example, if the second mutation is in the colon, then colon cancer may develop. If it is in the ovary, ovarian cancer may develop. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies of a particular mismatch-repair gene is just the first step in the process. What causes these additional mutations to be acquired is generally unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in DNA replication.

• #28 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The finding of MSI and/or absence of DNA MMR protein expression identifies that a tumor has lost DNA MMR function, and is the basis for differentiating familial CRC cases associated with Lynch syndrome from other HNPCC conditions. […] Lynch syndrome can be identified in 2%-3% of all CRC patients, and approximately 2% of all endometrial cancer patients, the two most common cancers observed with this syndrome. […] Patients can develop synchronous and metachronous cancers at relatively young ages, and Lynch-associated CRCs demonstrate accelerated neoplastic progression, with reports of cancers developing within 3 years after colonoscopy. […] Lynch syndrome is associated with germline mutations in one of the DNA MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM), and is transmitted in an autosomal dominant fashion.

• #29 Lynch Syndrome: An Updated Review

  https://www.mdpi.com/2073-4425/5/3/497

  Recently, constitutional 3′ deletions of EPCAM have been shown to cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. […] The normal function of the MMR proteins is to proofread the nucleotide sequence for potential base-base errors that occur during DNA synthesis. Defective MMR causes variations within the microsatellites, manifesting as a gain or loss in repeat length. This is described as microsatellite instability (MSI). […] Cancers that possess more than 40% microsatellite variations (i.e., positive for two or more of the five standard microsatellite markers routinely tested) are described as high frequency MSI (MSI-H). […] The effects were stronger in female carriers than in male carriers. Such modifiers may aid in identifying high-risk individuals who require more intensive surveillance.

• #30 Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-6-22

  Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. […] The main function of MMR is to maintain genomic stability by correcting mismatches generated during DNA replication. MMR malfunction results in a mutated phenotype and microsatellite instability (MSI), which promotes cancer formation. […] In endometrial cancers, MSI is very common and while a hallmark of LS, MSI is not equivalent to LS. MSI is also present in 15-25% of corresponding sporadic cancers. […] The majority of physicians and health care providers are not aware of the clinicopathologic features of LS-related EC. […] Based on the above characteristics, in endometrial cancers, MSI detection is not specific thus not very helpful in the diagnosis of LS.

• #31 Lynch Syndrome: An Updated Review

  https://www.mdpi.com/2073-4425/5/3/497

  Recently, constitutional 3′ deletions of EPCAM have been shown to cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. […] The normal function of the MMR proteins is to proofread the nucleotide sequence for potential base-base errors that occur during DNA synthesis. Defective MMR causes variations within the microsatellites, manifesting as a gain or loss in repeat length. This is described as microsatellite instability (MSI). […] Cancers that possess more than 40% microsatellite variations (i.e., positive for two or more of the five standard microsatellite markers routinely tested) are described as high frequency MSI (MSI-H). […] The effects were stronger in female carriers than in male carriers. Such modifiers may aid in identifying high-risk individuals who require more intensive surveillance.

• #32 Lynch syndrome | Concise Medical Knowledge

  https://www.lecturio.com/concepts/lynch-syndrome/

  Some mutated microsatellite sequences are associated with cell growth genes, leading to a benign then malignant neoplastic polyp/carcinoma. […] The MMR pathway of colon carcinogenesis is the 2nd-most common pathway of colorectal cancer, after the adenoma-carcinoma pathway of colon carcinogenesis. […] Loss of MMR activity causes an accumulation of DNA replication errors, particularly in repetitive sequences (tandem repeats). […] Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs. […] A cancer-driver mutation is eventually created by one of the uncorrected errors made during DNA replication. […] The protein products of mismatch repair (MMR) genes are important in spell-checking DNA during duplication by detecting and repairing DNA defects.

• #33 Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium | Journal of Hematology & Oncology | Full Text

  https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-6-22

  Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. […] The main function of MMR is to maintain genomic stability by correcting mismatches generated during DNA replication. MMR malfunction results in a mutated phenotype and microsatellite instability (MSI), which promotes cancer formation. […] In endometrial cancers, MSI is very common and while a hallmark of LS, MSI is not equivalent to LS. MSI is also present in 15-25% of corresponding sporadic cancers. […] The majority of physicians and health care providers are not aware of the clinicopathologic features of LS-related EC. […] Based on the above characteristics, in endometrial cancers, MSI detection is not specific thus not very helpful in the diagnosis of LS.

• #34 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  Tumors associated with germline MMR gene mutations can be differentiated from sporadic MSI CRCs on the basis of the absence of somatic BRAF mutations and absence of methylation of MLH1. […] The diagnosis of CMMRD is confirmed with detection of biallelic germline mutations in MMR genes; however the diagnosis is not always straightforward. […] Like tumors which develop in Lynch syndrome and Lynch-like syndrome, CMMRD CRCs display MSI, and immunohistochemistry will demonstrate absence of staining of the mutated MMR protein. […] CRCs are common, and thus may be seen in association with other hereditary cancer syndromes not typically associated with increased risk for colorectal neoplasia.

• #35 Lynch Syndrome: Signs/Symptoms, Causes, Outlook

  https://my.clevelandclinic.org/health/diseases/17195-lynch-syndrome-and-hnpcc

  Lynch syndrome affects your body’s ability to fix changes to your DNA within your cells. Lynch syndrome puts you at a high risk of developing cancer because your mismatch repair gene doesn’t have the tools to fix changes to your DNA. […] A genetic mutation (genetic change) in one of five genes that are responsible for fixing errors in DNA (mismatch repair gene) causes Lynch syndrome. If you have Lynch syndrome, your DNA mismatch repair gene (MMR) doesn’t have all the instructions to get rid of damaged cells, so they build up in your tissues and cause cancer.

• #36 Diagnosis and management of Lynch syndrome | Frontline Gastroenterology

  https://fg.bmj.com/content/13/e1/e80

  Lynch syndrome (LS) is a dominantly inherited cancer susceptibility syndrome defined by presence of pathogenic variants in DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2, or in deletions of the EPCAM gene. […] Recently, an appreciation of the mechanism of carcinogenesis in LS-associated cancers has contributed to the development of novel therapeutic and diagnostic approaches, with a gene-specific approach to disease management, with potential cancer-preventing vaccines in development. […] The cumulative lifetime incidence of CRC in people with LS (MLH1 45%, MSH2 35%, MSH6 20% PMS2 14%) is considerably higher than in the general population. […] Patients with LS have an accelerated pathway to carcinogenesis compared with the general population. […] The presence of dMMR indicates faulty DNA replication base pair mismatches, which have not been repaired.

• #37 Lynch Syndrome: An Updated Review

  https://www.mdpi.com/2073-4425/5/3/497

  Lynch syndrome is one of the most common cancer susceptibility syndromes. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. […] Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Also genomic rearrangements within the epithelial cell adhesion molecule gene EPCAM can lead to silencing of the closely linked MSH2 gene in EPCAM-expressing tissues. […] CRCs in Lynch syndrome are characterized by an adenoma-carcinoma progression ratio of 1:1 (estimated adenoma-cancer transformation time 1–3 years), as compared to sporadic cases that have a ratio of 30:1 (estimated adenoma-cancer transformation time 8–17 years). […] The majority of individuals with Lynch syndrome possess at least one pathogenic germline mutation of the MMR genes MLH1, MSH2, MSH6 or PMS2.

• #38 Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/188613-overview

  Although adenomas arise at the same rate in individuals with HNPCC as in the general population, they develop at a younger age (starting in the late second and early third decade of life) and progress to cancer far more rapidly. Carcinogenesis occurs over 2-3 years, compared with 8-10 years for sporadic adenomas.

• #39 Lynch Syndrome: An Updated Review

  https://www.mdpi.com/2073-4425/5/3/497

  Lynch syndrome is one of the most common cancer susceptibility syndromes. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. […] Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Also genomic rearrangements within the epithelial cell adhesion molecule gene EPCAM can lead to silencing of the closely linked MSH2 gene in EPCAM-expressing tissues. […] CRCs in Lynch syndrome are characterized by an adenoma-carcinoma progression ratio of 1:1 (estimated adenoma-cancer transformation time 1–3 years), as compared to sporadic cases that have a ratio of 30:1 (estimated adenoma-cancer transformation time 8–17 years). […] The majority of individuals with Lynch syndrome possess at least one pathogenic germline mutation of the MMR genes MLH1, MSH2, MSH6 or PMS2.

• #40 Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/188613-overview

  Although adenomas arise at the same rate in individuals with HNPCC as in the general population, they develop at a younger age (starting in the late second and early third decade of life) and progress to cancer far more rapidly. Carcinogenesis occurs over 2-3 years, compared with 8-10 years for sporadic adenomas.

• #41 Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/188613-overview

  Although adenomas arise at the same rate in individuals with HNPCC as in the general population, they develop at a younger age (starting in the late second and early third decade of life) and progress to cancer far more rapidly. Carcinogenesis occurs over 2-3 years, compared with 8-10 years for sporadic adenomas.

• #42 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The DNA MMR system provides recognition of post-DNA synthetic polymerase mistakes in the DNA strand at single base mispairs, chemotherapy-induced nucleotide alterations, and slippage mistakes at repetitive sequences termed microsatellites. […] Abrogation of DNA MMR function generates a hypermutated tumor that accumulates hundreds of random point mutations and frameshifts in the cells genome, and transition from an adenoma to CRC occurs at a rapid pace compared to MMR-intact tumors (1-3 years vs 1-2 decades, respectively). […] The biomarker assay that is used to determine loss of MMR function clinically is microsatellite instability (MSI), which detects acquired new frameshift length changes of microsatellites in neoplastic tissue compared to non-neoplastic tissue when MMR function is defective.

• #43 Lynch Syndrome (HNPCC) Causes | Stanford Health Care

  https://stanfordhealthcare.org/medical-conditions/cancer/lynch-syndrome/hnpcc-causes.html

  The majority of HNPCC cases are caused by mutations in one of several mismatch-repair genes: MSH2, MSH6, and PMS1 on chromosome 2, MLH1 on chromosome 3, MSH3 on chromosome 5, and PMS2 on chromosome 7. MLH1 and MSH2 are the genes most commonly implicated. Mutations in any one of these genes confers an increased lifetime risk to develop colorectal cancer and, in females, an increased risk to develop ovarian (12%) and endometrial (up to 60%) cancer. The genes responsible for HNPCC are mismatch-repair genes, which correct „spelling errors” in DNA that happen during the cell division process. When these genes are altered, or mutated, however, mismatches in the DNA remain. If mismatches accumulate in cell growth control genes, like proto-oncogenes and tumor suppressor genes, this will eventually lead to uncontrolled cell growth and tumor formation. Both copies of a mismatch-repair gene must be altered, or mutated, before a person will develop cancer.

• #44 Ovarian cancer – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/ovarian-cancer/symptoms-causes/syc-20375941

  Doctors know that ovarian cancer begins when cells in or near the ovaries develop changes (mutations) in their DNA. A cell’s DNA contains the instructions that tell the cell what to do. The changes tell the cells to grow and multiply quickly, creating a mass (tumor) of cancer cells. The cancer cells continue living when healthy cells would die. They can invade nearby tissues and break off from an initial tumor to spread (metastasize) to other parts of the body. […] Several other gene changes are known to increase the risk of ovarian cancer, including gene changes associated with Lynch syndrome and the genes BRIP1, RAD51C and RAD51D.

• #45 Lynch syndrome | Concise Medical Knowledge

  https://www.lecturio.com/concepts/lynch-syndrome/

  Some mutated microsatellite sequences are associated with cell growth genes, leading to a benign then malignant neoplastic polyp/carcinoma. […] The MMR pathway of colon carcinogenesis is the 2nd-most common pathway of colorectal cancer, after the adenoma-carcinoma pathway of colon carcinogenesis. […] Loss of MMR activity causes an accumulation of DNA replication errors, particularly in repetitive sequences (tandem repeats). […] Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs. […] A cancer-driver mutation is eventually created by one of the uncorrected errors made during DNA replication. […] The protein products of mismatch repair (MMR) genes are important in spell-checking DNA during duplication by detecting and repairing DNA defects.

• #46 Lynch syndrome | Concise Medical Knowledge

  https://www.lecturio.com/concepts/lynch-syndrome/

  Some mutated microsatellite sequences are associated with cell growth genes, leading to a benign then malignant neoplastic polyp/carcinoma. […] The MMR pathway of colon carcinogenesis is the 2nd-most common pathway of colorectal cancer, after the adenoma-carcinoma pathway of colon carcinogenesis. […] Loss of MMR activity causes an accumulation of DNA replication errors, particularly in repetitive sequences (tandem repeats). […] Microsatellite testing that shows mutations in 30% or more microsatellites is called microsatellite instability-high (MSI-H) and is the hallmark of defective MMRs. […] A cancer-driver mutation is eventually created by one of the uncorrected errors made during DNA replication. […] The protein products of mismatch repair (MMR) genes are important in spell-checking DNA during duplication by detecting and repairing DNA defects.

• #47 Lynch Syndrome AHS – M2004 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/lynch-syndrome

  The lifetime risk of colorectal cancer (CRC) is greatly increased in LS patients, but varies significantly from 10-74% dependent on which MMR gene is inactivated (Brosens et al., 2015). […] The histopathology of LS colorectal cancer is often poorly differentiated, with signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes, and a lymphoid host response to tumor (Peltomäki PT, 2010). […] The complexity of Lynch syndrome likewise evokes the use of complex diagnostic algorithms, oftentimes involving multiple subsequent germline and somatic tests. […] The utility and efficacy of these algorithms are also points of contention, given the novelty of said algorithms. […] The PREMM5 clinical prediction algorithm, available at http://premm.dfci.harvard.edu/, “estimates the cumulative probability of an individual carrying a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes” using an individual’s personal and family history of colorectal cancer, endometrial cancer, or other LS-related cancers with the results given as a percentage of overall predicted probability of mutation in one of the four LS-related genes (DFCI, 2020). […] Statistical models to predict risk of MMR mutations include PREMM5, MMRpredict, and MMRpro. […] The specificity and sensitivity of these methods can be polemical, and thus engender questions of what tests to even employ.

• #48 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The DNA MMR system provides recognition of post-DNA synthetic polymerase mistakes in the DNA strand at single base mispairs, chemotherapy-induced nucleotide alterations, and slippage mistakes at repetitive sequences termed microsatellites. […] Abrogation of DNA MMR function generates a hypermutated tumor that accumulates hundreds of random point mutations and frameshifts in the cells genome, and transition from an adenoma to CRC occurs at a rapid pace compared to MMR-intact tumors (1-3 years vs 1-2 decades, respectively). […] The biomarker assay that is used to determine loss of MMR function clinically is microsatellite instability (MSI), which detects acquired new frameshift length changes of microsatellites in neoplastic tissue compared to non-neoplastic tissue when MMR function is defective.

• #49 Lynch Syndrome AHS – M2004 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/lynch-syndrome

  The lifetime risk of colorectal cancer (CRC) is greatly increased in LS patients, but varies significantly from 10-74% dependent on which MMR gene is inactivated (Brosens et al., 2015). […] The histopathology of LS colorectal cancer is often poorly differentiated, with signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes, and a lymphoid host response to tumor (Peltomäki PT, 2010). […] The complexity of Lynch syndrome likewise evokes the use of complex diagnostic algorithms, oftentimes involving multiple subsequent germline and somatic tests. […] The utility and efficacy of these algorithms are also points of contention, given the novelty of said algorithms. […] The PREMM5 clinical prediction algorithm, available at http://premm.dfci.harvard.edu/, “estimates the cumulative probability of an individual carrying a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes” using an individual’s personal and family history of colorectal cancer, endometrial cancer, or other LS-related cancers with the results given as a percentage of overall predicted probability of mutation in one of the four LS-related genes (DFCI, 2020). […] Statistical models to predict risk of MMR mutations include PREMM5, MMRpredict, and MMRpro. […] The specificity and sensitivity of these methods can be polemical, and thus engender questions of what tests to even employ.

• #50 An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms | OMICS International

  https://www.omicsonline.org/an-update-on-the-pathogenesis-of-lynch-syndrome-recently-described-novel-molecular-mechanisms-2161-069X-3-151.php?aid=21289

  Recently, several novel genetic abnormalities have been identified which lead to the Lynch syndrome phenotype and may explain differences in the rates and risk of extracolonic malignancies. […] Among these novel mechanisms, EPCAM deletions, CHEK2 mutations, and germline promoter hypermethylation of MLH1 have been described with evidence that these are responsible for some of the MMR-negative cases.

• #51 The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors | Modern Pathology

  https://www.nature.com/articles/modpathol201230

  Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. […] We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. […] These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. […] Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage. […] Lynch syndrome-associated tumors are characterized by DNA mismatch repair deficiency, which results from a second somatic event inactivating the respective remaining functional mismatch repair gene allele.

• #52 Lynch syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/lynch-syndrome/

  Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer. […] Variants that cause a disease or increase the risk for a disease are sometimes called pathogenic variants. Pathogenic variants in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes can cause Lynch syndrome. […] The MLH1, MSH2, MSH6, and PMS2 genes are involved in repairing the errors that occur when DNA is copied in preparation for cell division, a process called DNA replication. Because these genes work together to fix DNA errors, they are known as mismatch repair (MMR) genes. Pathogenic variants in any of these MMR genes can cause Lynch syndrome. […] Changes in the EPCAM gene can also disrupt DNA repair, although the gene itself is not directly involved in this process. The EPCAM gene lies next to the MSH2 gene on chromosome 2, and certain EPCAM gene variants cause the MSH2 gene to be turned off (inactivated). As a result, the MSH2 gene’s role in DNA repair is disrupted, which can lead to accumulated DNA errors and cancer development.

• #53 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  When MMR genes become mutated, several specific genes contain microsatellites in their coding region and become susceptible to the accumulation of mutations. […] The key differentiating factor is that sporadic cancers are the result of somatic hypermethylation rather than germ-line hypermethylation. […] Historically, the underlying mechanism for Lynch syndrome is the result of an autosomal dominant DNA mismatch repair [MMR] deficiency with resultant tumor microsatellite instability [MSI]. […] Current data suggests that 10 to 40% of the patients with early-onset colorectal cancer (mean age 43), and malignancies involving the duodenum, ileum, appendix, endometrium, and bladder may have an EPCAM mutation. […] Another intriguing mechanism for Lynch syndrome is the germ-line promoter hypermethylation of MLH1. […] The exact phenotype, tumor spectrum, and incidence remain to be defined for germ-line hypermethylation.

• #54 Recent advances in Lynch syndrome | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00231-4

  Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. […] The function of DNA MMR is to maintain genomic stability, and the dysfunction of DNA MMR could lead to alterations in the repetitive sequence number of microsatellites, which is defined as microsatellite instability (MSI). […] Commonly, high frequency of MSI (MSI-H) is shown in tumors developed in LS individuals with variants in MMR genes. […] The cumulative cancer incidences of MLH1, MSH2, MSH6, or PMS2 variant carriers up to age 75 are as follows: MLH1: 81% (females), 71.4% (males); MSH2: 84.3% (females), 75.2% (males); MSH6: 61.8% (females), 41.7% (males); and PMS2: 34.1% (both sexes). […] A study showed that a significant proportion of patients with Bethesda criteria who have loss of MLH1 protein expression in their tumors and do not have an MLH1 pathogenic germline mutation display constitutional MLH1 methylation as the mechanism of Lynch syndrome. […] EPCAM deletion usually rarely causes extragastrointestinal tumors. […] Studies have reported that although PMS2 pathogenic variant carriers may not increase the tumorigenesis of CRC, the lack of PMS2 protein can promote the progression of MMR mature adenoma to CRC.

• #55 The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors | Modern Pathology

  https://www.nature.com/articles/modpathol201230

  The detection of a somatic mutational event causing MSH2 inactivation in one of the EPCAM-positive tumors (adenoma from patient 1) explains why some tumors from EPCAM germline deletion carriers show loss of MSH2, but retained EPCAM expression. […] The frequent occurrence of somatic deletions affecting the EPCAM gene as a second hit in tumors from EPCAM deletion carriers suggests that the localization of somatic events inactivating mismatch repair genes in Lynch syndrome is not random, but related to the underlying germline mutation. […] This strongly supports the hypothesis that gene conversion is a common mechanism of mismatch repair gene inactivation in Lynch syndrome-associated tumors, demonstrating that this mechanism of locus-restricted recombination is also responsible for MSH2 inactivation in tumors from EPCAM deletion carriers. […] In summary, we demonstrate that lack of EPCAM protein expression in tumors from EPCAM deletion carriers requires biallelic EPCAM deletion, resulting from the combination of a germline and a second somatic deletion, both affecting the EPCAM gene.

• #56 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Cell cycle check point kinase 2 (CHEK2) is yet another alternative mechanism for early-onset cancer with a Lynch phenotype. […] This finding has led to consideration of an alternative pathway to Lynch syndrome, not previously identified. […] The classic pathway for development of Lynch syndrome cancers is through the accumulation of mismatched bases in microsatellite areas of DNA secondary to an inherited defect in mismatch repair mechanisms. […] Other genetic mutations continue to be identified, which account for a smaller percentage of HNPCC cancers, but remain important for the diagnosis and screening of patients and their families.

• #57 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Cell cycle check point kinase 2 (CHEK2) is yet another alternative mechanism for early-onset cancer with a Lynch phenotype. […] This finding has led to consideration of an alternative pathway to Lynch syndrome, not previously identified. […] The classic pathway for development of Lynch syndrome cancers is through the accumulation of mismatched bases in microsatellite areas of DNA secondary to an inherited defect in mismatch repair mechanisms. […] Other genetic mutations continue to be identified, which account for a smaller percentage of HNPCC cancers, but remain important for the diagnosis and screening of patients and their families.

• #58 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Cell cycle check point kinase 2 (CHEK2) is yet another alternative mechanism for early-onset cancer with a Lynch phenotype. […] This finding has led to consideration of an alternative pathway to Lynch syndrome, not previously identified. […] The classic pathway for development of Lynch syndrome cancers is through the accumulation of mismatched bases in microsatellite areas of DNA secondary to an inherited defect in mismatch repair mechanisms. […] Other genetic mutations continue to be identified, which account for a smaller percentage of HNPCC cancers, but remain important for the diagnosis and screening of patients and their families.

• #59 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  When MMR genes become mutated, several specific genes contain microsatellites in their coding region and become susceptible to the accumulation of mutations. […] The key differentiating factor is that sporadic cancers are the result of somatic hypermethylation rather than germ-line hypermethylation. […] Historically, the underlying mechanism for Lynch syndrome is the result of an autosomal dominant DNA mismatch repair [MMR] deficiency with resultant tumor microsatellite instability [MSI]. […] Current data suggests that 10 to 40% of the patients with early-onset colorectal cancer (mean age 43), and malignancies involving the duodenum, ileum, appendix, endometrium, and bladder may have an EPCAM mutation. […] Another intriguing mechanism for Lynch syndrome is the germ-line promoter hypermethylation of MLH1. […] The exact phenotype, tumor spectrum, and incidence remain to be defined for germ-line hypermethylation.

• #60 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  When MMR genes become mutated, several specific genes contain microsatellites in their coding region and become susceptible to the accumulation of mutations. […] The key differentiating factor is that sporadic cancers are the result of somatic hypermethylation rather than germ-line hypermethylation. […] Historically, the underlying mechanism for Lynch syndrome is the result of an autosomal dominant DNA mismatch repair [MMR] deficiency with resultant tumor microsatellite instability [MSI]. […] Current data suggests that 10 to 40% of the patients with early-onset colorectal cancer (mean age 43), and malignancies involving the duodenum, ileum, appendix, endometrium, and bladder may have an EPCAM mutation. […] Another intriguing mechanism for Lynch syndrome is the germ-line promoter hypermethylation of MLH1. […] The exact phenotype, tumor spectrum, and incidence remain to be defined for germ-line hypermethylation.

• #61 Recent advances in Lynch syndrome | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00231-4

  Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. […] The function of DNA MMR is to maintain genomic stability, and the dysfunction of DNA MMR could lead to alterations in the repetitive sequence number of microsatellites, which is defined as microsatellite instability (MSI). […] Commonly, high frequency of MSI (MSI-H) is shown in tumors developed in LS individuals with variants in MMR genes. […] The cumulative cancer incidences of MLH1, MSH2, MSH6, or PMS2 variant carriers up to age 75 are as follows: MLH1: 81% (females), 71.4% (males); MSH2: 84.3% (females), 75.2% (males); MSH6: 61.8% (females), 41.7% (males); and PMS2: 34.1% (both sexes). […] A study showed that a significant proportion of patients with Bethesda criteria who have loss of MLH1 protein expression in their tumors and do not have an MLH1 pathogenic germline mutation display constitutional MLH1 methylation as the mechanism of Lynch syndrome. […] EPCAM deletion usually rarely causes extragastrointestinal tumors. […] Studies have reported that although PMS2 pathogenic variant carriers may not increase the tumorigenesis of CRC, the lack of PMS2 protein can promote the progression of MMR mature adenoma to CRC.

• #62 Epimutation and cancer: a new carcinogenic mechanism of Lynch syndrome (Review)

  https://www.spandidos-publications.com/10.3892/ijo.2012.1528

  Epimutation is defined as abnormal transcriptional repression of active genes and/or abnormal activation of usually repressed genes caused by errors in epigenetic gene repression. […] Cancers associated with epimutation include Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC), chronic lymphocytic leukemia, breast cancer and ovarian cancer. […] Epimutation of DNA mismatch repair (MMR) genes (BRCA1, hMLH1 and hMSH2) involved in development familial cancers has also been found. […] Lynch syndrome (HNPCC) is a typical familial tumor with autosomal dominant inheritance. […] Aberrant mismatch repair (MMR) genes are involved in carcinogenesis of Lynch syndrome. […] Recently, a new type of Lynch syndrome has been found with no pathologic mutation in MMR genes, but epimutation in the promoter region of hMLH1 or hMSH2. […] This finding suggested that epimutation in germline hMLH1 can be a cause of Lynch syndrome.

• #63 New Lynch syndrome subtype discovered: Implications for cancer treatment, prevention, and family planning

  https://medicine.unimelb.edu.au/school-structure/clinical-pathology/news-and-events/new-lynch-syndrome-subtype-discovered

  Researchers have identified a new mechanism causing Lynch syndrome, the most common hereditary cancer syndrome predisposing people to cancers of the bowel and endometrium. […] This study identified the first reported case of post-zygotic mosaicism in Lynch syndrome isolated to a segment of the colon, termed localised mosaicism. […] Dr Walker said that identifying this first reported case of localised MMR gene mosaicism has important clinical implications. […] „This discovery provides an opportunity to tailor clinical management differently from the intensive standard of care typically recommended for Lynch syndrome patients. It could inform treatments that may reduce the risk of developing a second primary colorectal cancer,” said Dr Walker. […] This research follows on from Dr Walker’s earlier work which identified the first-ever case of soma-wide mosaicism in the MSH6 gene. It significantly furthered the understanding of both localised and soma-wide (affecting the entire body) mosaicism in Lynch syndrome providing guidance on when mosaicism should be investigated in the diagnostic setting. […] „Identifying mosaicism is crucial for patients,” said Dr. Walker. „However, due to its low prevalence in Lynch syndrome and the multiple tests required that are performed in a step-wise approach, our findings support a targeted approach to mosaicism testing.

• #64 New Lynch syndrome subtype discovered: Implications for cancer treatment, prevention, and family planning

  https://medicine.unimelb.edu.au/school-structure/clinical-pathology/news-and-events/new-lynch-syndrome-subtype-discovered

  Researchers have identified a new mechanism causing Lynch syndrome, the most common hereditary cancer syndrome predisposing people to cancers of the bowel and endometrium. […] This study identified the first reported case of post-zygotic mosaicism in Lynch syndrome isolated to a segment of the colon, termed localised mosaicism. […] Dr Walker said that identifying this first reported case of localised MMR gene mosaicism has important clinical implications. […] „This discovery provides an opportunity to tailor clinical management differently from the intensive standard of care typically recommended for Lynch syndrome patients. It could inform treatments that may reduce the risk of developing a second primary colorectal cancer,” said Dr Walker. […] This research follows on from Dr Walker’s earlier work which identified the first-ever case of soma-wide mosaicism in the MSH6 gene. It significantly furthered the understanding of both localised and soma-wide (affecting the entire body) mosaicism in Lynch syndrome providing guidance on when mosaicism should be investigated in the diagnostic setting. […] „Identifying mosaicism is crucial for patients,” said Dr. Walker. „However, due to its low prevalence in Lynch syndrome and the multiple tests required that are performed in a step-wise approach, our findings support a targeted approach to mosaicism testing.

• #65 Lynch-like Syndrome: Potential Mechanisms and Management

  https://www.mdpi.com/2072-6694/14/5/1115

  Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. […] Lynch-like syndrome (LLS) is defined as colorectal cancer cases with microsatellite instability (MSI) and loss of expression of MLH1, MSH2, MSH6, or PMS2 by immunohistochemistry (IHC) in the absence of a germline mutation in these genes that cannot be explained by BRAF mutation or MLH1 hypermethylation. […] Managing these cases is challenging because the subsequent carcinogenic process is yet to be unveiled. LLS is probably caused by somatic mutations in the mismatch repair (MMR) genes, and, therefore, it is sporadic. […] However, patients with LLS and their relatives have an increased risk of colorectal cancer (CRC), suggesting a possibility of inherited risk.

• #66 Lynch-like Syndrome: Potential Mechanisms and Management

  https://www.mdpi.com/2072-6694/14/5/1115

  Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. […] Lynch-like syndrome (LLS) is defined as colorectal cancer cases with microsatellite instability (MSI) and loss of expression of MLH1, MSH2, MSH6, or PMS2 by immunohistochemistry (IHC) in the absence of a germline mutation in these genes that cannot be explained by BRAF mutation or MLH1 hypermethylation. […] Managing these cases is challenging because the subsequent carcinogenic process is yet to be unveiled. LLS is probably caused by somatic mutations in the mismatch repair (MMR) genes, and, therefore, it is sporadic. […] However, patients with LLS and their relatives have an increased risk of colorectal cancer (CRC), suggesting a possibility of inherited risk.

• #67 Lynch-like Syndrome: Potential Mechanisms and Management

  https://www.mdpi.com/2072-6694/14/5/1115

  The most probable scenario is that LLS represents a mixture of sporadic MSI cases, unidentified Lynch syndrome (LS) cases, and possibly other hereditary cases of yet-to-be-determined origin. […] Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. […] This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity. […] Up to 50% of cases of suspected LS in patients with CRC that test positive for MMR-D by IHC or MSI do not have any germline mutation in an MMR gene, BRAF alteration or MLH1 hypermethylation.

• #68 Lynch-like Syndrome: Potential Mechanisms and Management

  https://www.mdpi.com/2072-6694/14/5/1115

  These cases are defined as Lynch-like syndrome (LLS). LLS possibly describes a heterogeneous group of conditions that possibly includes a mix between sporadic and hereditary cases. […] The risk of developing CRC and other LS-related cancers in LLS cohorts and their first-degree relatives is lower than in LS patients. […] However, LLS patients are more likely to have CRC than sporadic cases. […] LLS tumors share the pathological characteristics of MSI CRC, as they are mainly located on the proximal colon, frequently have a large size, and usually present a higher concentration of infiltrated lymphocytes. […] Different plausible causes to explain the origin of LLS tumors have been described. […] According to the hereditary origin, unknown mechanisms or germline mutations in other genes than those involved in the classical MMR system could mimic the Lynch phenotype with MMR-D.

• #69 Lynch-like Syndrome: Potential Mechanisms and Management

  https://www.mdpi.com/2072-6694/14/5/1115

  In addition, some LLS cases could be LS with unidentified germline MMR mutations. […] In contrast, LLS could be due to somatic defects in genes related to tumor onset and progression or due to biallelic alterations in MMR genes outside MLH1 promoter methylation, thus having a sporadic origin. […] A frequent explanation for LLS cases that should always be ruled out is false-positive IHC/MSI results, which represent approximately 19% of cases in some series. […] Recent studies have shown that somatic mutations in MMR genes are responsible for a proportion of LLS cases. […] It seems that the most common double somatic hit is a somatic mutation combined with LOH, followed by two somatic mutations. […] Based on these studies, the number of cases explained by somatic inactivation could be approximately 50% of LLS tumors. […] Therefore, there is a subgroup of LLS that can be explained by double somatic inactivation, and these cases should probably be excluded from the LLS classification due to the probable sporadic origin.

• #70 Molecular Mechanism of Lynch Syndrome | SpringerLink

  https://link.springer.com/chapter/10.1007/978-981-15-6891-6_1

  Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss of function of one of four different protein (MLH1, MSH2, MSH6, and PMS2), which are the products of mismatch repair genes. […] An abnormal EPCAM gene at the position adjacent to the MSH2 gene also inhibits MSH2 expression and causes Lynch syndrome. […] Lynch syndrome is a state of mismatch repair deficiency (MMRd) due to a monoallelic abnormality of the mismatch repair genes. […] The phenotype indicating the mismatch repair deficiency can be frequently observed as a microsatellite instability (MSI) in tumors. […] Generally, Lynch syndrome develops in adulthood, but MMR gene abnormalities are observed in children with different genotypes and phenotypes. […] This condition is called constitutional mismatch repair deficiency (CMMRD).

• #71

  https://dokumen.pub/lynch-syndrome-molecular-mechanism-and-current-clinical-practice-1st-ed-9789811568909-9789811568916.html

  Mismatch repair proteins are involved in repairing of incorrect pairing, including point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites, that can arise during DNA replication. […] Lynch syndrome develops in adulthood, but MMR gene abnormalities are observed in children with different genotypes and phenotypes. […] The phenotype indicating the mismatch repair deficiency can be frequently observed as a microsatellite instability (MSI) in tumors. […] Lynch syndrome is a state of mismatch repair deficiency (MMRd) due to a monoallelic abnormality of the mismatch repair genes. […] The mismatch repair system consists of sequential steps for the recognition, removal, and resynthesis of the mismatch site in DNA. […] The MMR proteins relevant to Lynch syndrome act as heterodimers.

• #72 Lynch Syndrome Cancers & Genetic Testing | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/cancer-care/risk-assessment-screening/genetic-counseling-and-testing/hereditary-cancer-genes-and-hereditary-cancer-syndromes/lynch-syndrome

  Distinct variations of Lynch syndrome include other features: Muir-Torre syndrome is associated with the standard Lynch syndromerelated cancers and a type of skin cancer called sebaceous gland lesions. […] People with CMMR-D have mutations in both copies of one of the Lynch syndrome genes (one from each parent), while people with typical Lynch syndrome carry only one mutation (from just one parent). […] We recommend that people with Lynch syndrome pursue specialized cancer surveillance examinations. This includes colonoscopy, upper endoscopy, and urine testing. […] Recommendations on the best way for you to manage your individual cancer risk should be discussed with a genetic counselor or doctor who is experienced in the care of people with Lynch syndrome. […] Lynch syndrome can be passed from a mother or father to a son or daughter. People with a first-degree relative (a parent, sibling, or child) with Lynch syndrome have a 50% chance of having inherited it.

• #73

  https://dokumen.pub/lynch-syndrome-molecular-mechanism-and-current-clinical-practice-1st-ed-9789811568909-9789811568916.html

  The inactivation of MSH2 leads to the inability to form MutS complexes and the concurrent loss of MSH2 and MSH6. […] The MMR pathway corrects single basebase or insertion/deletion (indel) mismatches resulted from misincorporation by DNA polymerases during DNA replication. […] The MMR pathway is one of the major DNA repair mechanisms which is conserved from prokaryotes to higher eukaryotes. […] Lynch syndrome is caused by germline pathogenic variants in the mismatch repair (MMR) genes. […] The MMR pathway corrects single basebase or insertion/deletion (indel) mismatches resulted from misincorporation by DNA polymerases during DNA replication. […] The spectrum of cancers observed in patients with CMMRD is apparently different from that found in LS. […] The MMR pathway is one of the major DNA repair mechanisms which is conserved from prokaryotes to higher eukaryotes.

• #74 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  Tumors associated with germline MMR gene mutations can be differentiated from sporadic MSI CRCs on the basis of the absence of somatic BRAF mutations and absence of methylation of MLH1. […] The diagnosis of CMMRD is confirmed with detection of biallelic germline mutations in MMR genes; however the diagnosis is not always straightforward. […] Like tumors which develop in Lynch syndrome and Lynch-like syndrome, CMMRD CRCs display MSI, and immunohistochemistry will demonstrate absence of staining of the mutated MMR protein. […] CRCs are common, and thus may be seen in association with other hereditary cancer syndromes not typically associated with increased risk for colorectal neoplasia.

• #75 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  Tumors associated with germline MMR gene mutations can be differentiated from sporadic MSI CRCs on the basis of the absence of somatic BRAF mutations and absence of methylation of MLH1. […] The diagnosis of CMMRD is confirmed with detection of biallelic germline mutations in MMR genes; however the diagnosis is not always straightforward. […] Like tumors which develop in Lynch syndrome and Lynch-like syndrome, CMMRD CRCs display MSI, and immunohistochemistry will demonstrate absence of staining of the mutated MMR protein. […] CRCs are common, and thus may be seen in association with other hereditary cancer syndromes not typically associated with increased risk for colorectal neoplasia.

• #76

  https://link.springer.com/article/10.1007/s10689-013-9635-x

  The majority of Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), has been linked to heterozygous defects in DNA mismatch repair (MMR). […] Loss-of-heterozygosity (LOH) that retains the mutant MMR allele and epigenetic silencing of MMR genes are associated with an increased mutation rate that drives carcinogenesis as well as microsatellite instability that is a hallmark of LS/HNPCC. […] Understanding the biophysical functions of the MMR components is crucial to elucidating the role of MMR in human tumorigenesis and determining the pathogenetic consequences of patients that present in the clinic with an uncharacterized variant of the MMR genes. […] We summarize the historical association between LS/HNPCC and MMR, discuss the mechanism of the MMR and finally examine the functional analysis of MMR defects found in LS/HNPCC patients and their relationship with the severity of the disease.

• #77 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The finding of MSI and/or absence of DNA MMR protein expression identifies that a tumor has lost DNA MMR function, and is the basis for differentiating familial CRC cases associated with Lynch syndrome from other HNPCC conditions. […] Lynch syndrome can be identified in 2%-3% of all CRC patients, and approximately 2% of all endometrial cancer patients, the two most common cancers observed with this syndrome. […] Patients can develop synchronous and metachronous cancers at relatively young ages, and Lynch-associated CRCs demonstrate accelerated neoplastic progression, with reports of cancers developing within 3 years after colonoscopy. […] Lynch syndrome is associated with germline mutations in one of the DNA MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM), and is transmitted in an autosomal dominant fashion.

• #78 Lynch syndrome – Libre Pathology

  https://librepathology.org/wiki/Lynch_syndrome

  Lynch syndrome, also hereditary non-polyposis colorectal cancer syndrome (abbreviated HNPCC), is a constellation of clinical findings caused by a mutation in a mismatch repair gene, of which there are several. […] Definitive diagnosis is by molecular testing (sequencing). […] Immunohistochemical stains have a very strong concordance with molecular testing – see microsatellite instability. […] Muir-Torre syndrome is a subset of HNPCC that includes the presence of sebaceous adenomas, and sebaceous carcinomas. […] MTS is caused by mutations in MSH2 or MLH1.

• #79 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The finding of MSI and/or absence of DNA MMR protein expression identifies that a tumor has lost DNA MMR function, and is the basis for differentiating familial CRC cases associated with Lynch syndrome from other HNPCC conditions. […] Lynch syndrome can be identified in 2%-3% of all CRC patients, and approximately 2% of all endometrial cancer patients, the two most common cancers observed with this syndrome. […] Patients can develop synchronous and metachronous cancers at relatively young ages, and Lynch-associated CRCs demonstrate accelerated neoplastic progression, with reports of cancers developing within 3 years after colonoscopy. […] Lynch syndrome is associated with germline mutations in one of the DNA MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM), and is transmitted in an autosomal dominant fashion.

• #80 Lynch Syndrome AHS – M2004 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/lynch-syndrome

  The lifetime risk of colorectal cancer (CRC) is greatly increased in LS patients, but varies significantly from 10-74% dependent on which MMR gene is inactivated (Brosens et al., 2015). […] The histopathology of LS colorectal cancer is often poorly differentiated, with signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes, and a lymphoid host response to tumor (Peltomäki PT, 2010). […] The complexity of Lynch syndrome likewise evokes the use of complex diagnostic algorithms, oftentimes involving multiple subsequent germline and somatic tests. […] The utility and efficacy of these algorithms are also points of contention, given the novelty of said algorithms. […] The PREMM5 clinical prediction algorithm, available at http://premm.dfci.harvard.edu/, “estimates the cumulative probability of an individual carrying a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes” using an individual’s personal and family history of colorectal cancer, endometrial cancer, or other LS-related cancers with the results given as a percentage of overall predicted probability of mutation in one of the four LS-related genes (DFCI, 2020). […] Statistical models to predict risk of MMR mutations include PREMM5, MMRpredict, and MMRpro. […] The specificity and sensitivity of these methods can be polemical, and thus engender questions of what tests to even employ.

• #81 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  Germline testing for mutations in the MMR genes is the gold standard for characterizing Lynch syndrome, and can be identified in 80% of Lynch kindreds. […] Specific mutations of DNA MMR genes are associated with differences in phenotype of Lynch patients. […] Family history-based clinical criteria, such as the Amsterdam criteria (3 relatives with CRC, across 2 generations, with one case diagnosed at age 50 years) and/or Bethesda guidelines, have limited sensitivity and identify only a portion of MMR mutation carriers. […] Given that intensive surveillance with colonoscopy every 1-2 years has been shown to decrease morbidity and mortality in families with Lynch syndrome, universal testing of all CRC tumors for MMR deficiency has been proposed as a cost-effective strategy to screen for Lynch syndrome.

• #82 Urologic implications of Lynch syndrome

  https://www.urologytimes.com/view/urologic-implications-of-lynch-syndrome

  The risk of developing UTUC in a patient with LS is about 22 times higher than that of the general population and is estimated at between 0.4% and 20%. A review of 288 patients with LS in Denmark showed that 22% developed UTUC and 17% developed urothelial carcinoma of the bladder. […] Genetic testing for MMR mutations should be performed in certain patients with UTUC. […] Inclusion of prostate cancer as an LS-associated cancer remains controversial despite being clearly defined by Ryan et al in 2014. This meta-analysis and systematic review showed that there is a 3.67-fold relative risk for developing prostate cancer in patients with MMR mutations, especially MSH2. […] Patients with UTUC or prostate cancer meeting the Amsterdam II criteria or having abnormal immunohistochemical testing on pathology should undergo genetic screening for LS. […] Lynch syndrome is one of the most common hereditary malignancy syndromes and is associated with multiple urologic cancers.

• #83 Diagnosis and management of Lynch syndrome | Frontline Gastroenterology

  https://fg.bmj.com/content/13/e1/e80

  Lynch syndrome (LS) is a dominantly inherited cancer susceptibility syndrome defined by presence of pathogenic variants in DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2, or in deletions of the EPCAM gene. […] Recently, an appreciation of the mechanism of carcinogenesis in LS-associated cancers has contributed to the development of novel therapeutic and diagnostic approaches, with a gene-specific approach to disease management, with potential cancer-preventing vaccines in development. […] The cumulative lifetime incidence of CRC in people with LS (MLH1 45%, MSH2 35%, MSH6 20% PMS2 14%) is considerably higher than in the general population. […] Patients with LS have an accelerated pathway to carcinogenesis compared with the general population. […] The presence of dMMR indicates faulty DNA replication base pair mismatches, which have not been repaired.

• #84 High predictability for identifying Lynch syndrome via microsatellite instability testing or immunohistochemistry in all Lynch-associated tumor types – Carethers – Translational Cancer Research

  https://tcr.amegroups.org/article/view/30800/html

  Both tests individually are used to screen CRCs and ECs for potential Lynch syndrome patients, with both a great improvement upon solely using the clinically-oriented Amsterdam criteria or Bethesda guidelines. CRCs and ECs that show MSI and/or MMR protein expression loss via immunohistochemistry (IHC) should inform the need for genetic counseling and genetic testing for a germline MMR gene mutation, the ultimate gold standard for characterizing Lynch syndrome families. […] Patients whose tumors show MSI-high, which includes all Lynch syndrome patients, may obtain a survival benefit with immune checkpoint blockade due to the hypermutated nature of the tumors and the generation of neoantigens from transcribed and subsequently translated genes that contain microsatellite coding sequences.

• #85 Diagnosis and management of Lynch syndrome | Frontline Gastroenterology

  https://fg.bmj.com/content/13/e1/e80

  The optimal pathway is that genomic testing be offered locally by the gastroenterologist, or other CRC multidisciplinary team (MDT) member, a process called mainstreaming, but patients may alternatively be referred to a clinical genetics team. […] The advent of checkpoint inhibitor immunotherapy is a significant recent advance in dMMR CRC as well as across a range of dMMR cancers.

• #86 Preventing Lynch Syndrome Cancers: New Study Suggests Immunotherapy Could Work | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/news/preventing-lynch-syndrome-cancers-new-study-suggests-immunotherapy-could-work

  Immunotherapy drugs called checkpoint inhibitors may prevent serious tumors from forming in some people with an increased risk of cancer due to a condition called Lynch syndrome, according to new research published October 16, 2023, in Nature Medicine by Memorial Sloan Kettering Cancer Center (MSK). […] People with Lynch syndrome have such a high risk of developing cancer because they carry a gene mutation that prevents their cells from being able to repair genetic damage. This leads to a condition called DNA mismatch repair deficiency (MMRd). […] These MMRd cancers have a lot of mutations, which makes them visible to the immune system. Therefore, drugs that enlist the immune system to fight cancer cells are particularly effective. Past research from Dr. Diaz and others found that tumors with MMRd are more likely to respond to checkpoint inhibitors. Thanks to that discovery, these drugs are now widely used to treat patients whose tumors have MMRd, including those whose cancers are due to Lynch syndrome.

• #87 Diagnosis and management of Lynch syndrome | Frontline Gastroenterology

  https://fg.bmj.com/content/13/e1/e80

  The optimal pathway is that genomic testing be offered locally by the gastroenterologist, or other CRC multidisciplinary team (MDT) member, a process called mainstreaming, but patients may alternatively be referred to a clinical genetics team. […] The advent of checkpoint inhibitor immunotherapy is a significant recent advance in dMMR CRC as well as across a range of dMMR cancers.

• #88 Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications | European Journal of Human Genetics

  https://www.nature.com/articles/5201584

  Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). […] Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. […] The presence of a deleterious germline mutation in the patient/family will enable a high level of diagnostic certainty in hereditary CRC syndromes such as FAP with its APC mutation, and the Lynch syndrome with mutations in mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2). […] Molecular genetic heterogeneity must be considered when assessing the Lynch syndrome cancer phenotype. […] Current data suggest that MLH1 mutations have a higher expression of CRC than do MSH2 mutations, which have more extracolonic cancers and MuirTorre features. […] MSH6 mutations, when compared with those of MLH1 and MSH2, show a lower expression of CRC but an excess of endometrial cancer.

• #89 Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications | European Journal of Human Genetics

  https://www.nature.com/articles/5201584

  The phenotypic consequences of PMS2 mutations appear to be highly variable, often with childhood onset of atypical tumors, but the number of observations is too limited for firm conclusions at this time. […] The major MMR genes that harbor causal mutations for Lynch syndrome are MSH2, MLH1, MSH6 and PMS2. […] Individuals with such mutations have an 70%85% risk, based on the mutation’s penetrance, to develop CRC by the age of 60 years. […] The predictive power of MSI and/or IHC for loss of MMR gene expression must be considered and have been found to be increasingly helpful in this regard. […] The presence of major clues such as fulfillment of the Amsterdam criteria, very early age at onset, multiple primary cancers that are integral to Lynch syndrome, and/or the presence of key pathologic features, collectively may provide a basis for MMR gene testing.

• #90 Recent advances in Lynch syndrome | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00231-4

  Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. […] The function of DNA MMR is to maintain genomic stability, and the dysfunction of DNA MMR could lead to alterations in the repetitive sequence number of microsatellites, which is defined as microsatellite instability (MSI). […] Commonly, high frequency of MSI (MSI-H) is shown in tumors developed in LS individuals with variants in MMR genes. […] The cumulative cancer incidences of MLH1, MSH2, MSH6, or PMS2 variant carriers up to age 75 are as follows: MLH1: 81% (females), 71.4% (males); MSH2: 84.3% (females), 75.2% (males); MSH6: 61.8% (females), 41.7% (males); and PMS2: 34.1% (both sexes). […] A study showed that a significant proportion of patients with Bethesda criteria who have loss of MLH1 protein expression in their tumors and do not have an MLH1 pathogenic germline mutation display constitutional MLH1 methylation as the mechanism of Lynch syndrome. […] EPCAM deletion usually rarely causes extragastrointestinal tumors. […] Studies have reported that although PMS2 pathogenic variant carriers may not increase the tumorigenesis of CRC, the lack of PMS2 protein can promote the progression of MMR mature adenoma to CRC.

• #91 Lynch Syndrome AHS – M2004 | Providers | Blue Cross NC

  https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/lynch-syndrome

  The lifetime risk of colorectal cancer (CRC) is greatly increased in LS patients, but varies significantly from 10-74% dependent on which MMR gene is inactivated (Brosens et al., 2015). […] The histopathology of LS colorectal cancer is often poorly differentiated, with signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes, and a lymphoid host response to tumor (Peltomäki PT, 2010). […] The complexity of Lynch syndrome likewise evokes the use of complex diagnostic algorithms, oftentimes involving multiple subsequent germline and somatic tests. […] The utility and efficacy of these algorithms are also points of contention, given the novelty of said algorithms. […] The PREMM5 clinical prediction algorithm, available at http://premm.dfci.harvard.edu/, “estimates the cumulative probability of an individual carrying a germline mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes” using an individual’s personal and family history of colorectal cancer, endometrial cancer, or other LS-related cancers with the results given as a percentage of overall predicted probability of mutation in one of the four LS-related genes (DFCI, 2020). […] Statistical models to predict risk of MMR mutations include PREMM5, MMRpredict, and MMRpro. […] The specificity and sensitivity of these methods can be polemical, and thus engender questions of what tests to even employ.

• #92 Recent advances in Lynch syndrome | Experimental Hematology & Oncology | Full Text

  https://ehoonline.biomedcentral.com/articles/10.1186/s40164-021-00231-4

  Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. […] The function of DNA MMR is to maintain genomic stability, and the dysfunction of DNA MMR could lead to alterations in the repetitive sequence number of microsatellites, which is defined as microsatellite instability (MSI). […] Commonly, high frequency of MSI (MSI-H) is shown in tumors developed in LS individuals with variants in MMR genes. […] The cumulative cancer incidences of MLH1, MSH2, MSH6, or PMS2 variant carriers up to age 75 are as follows: MLH1: 81% (females), 71.4% (males); MSH2: 84.3% (females), 75.2% (males); MSH6: 61.8% (females), 41.7% (males); and PMS2: 34.1% (both sexes). […] A study showed that a significant proportion of patients with Bethesda criteria who have loss of MLH1 protein expression in their tumors and do not have an MLH1 pathogenic germline mutation display constitutional MLH1 methylation as the mechanism of Lynch syndrome. […] EPCAM deletion usually rarely causes extragastrointestinal tumors. […] Studies have reported that although PMS2 pathogenic variant carriers may not increase the tumorigenesis of CRC, the lack of PMS2 protein can promote the progression of MMR mature adenoma to CRC.

• #93 Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

  https://www.wjgnet.com/1007-9327/full/v21/i31/9253.htm

  The finding of MSI and/or absence of DNA MMR protein expression identifies that a tumor has lost DNA MMR function, and is the basis for differentiating familial CRC cases associated with Lynch syndrome from other HNPCC conditions. […] Lynch syndrome can be identified in 2%-3% of all CRC patients, and approximately 2% of all endometrial cancer patients, the two most common cancers observed with this syndrome. […] Patients can develop synchronous and metachronous cancers at relatively young ages, and Lynch-associated CRCs demonstrate accelerated neoplastic progression, with reports of cancers developing within 3 years after colonoscopy. […] Lynch syndrome is associated with germline mutations in one of the DNA MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM), and is transmitted in an autosomal dominant fashion.

• #94 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Cell cycle check point kinase 2 (CHEK2) is yet another alternative mechanism for early-onset cancer with a Lynch phenotype. […] This finding has led to consideration of an alternative pathway to Lynch syndrome, not previously identified. […] The classic pathway for development of Lynch syndrome cancers is through the accumulation of mismatched bases in microsatellite areas of DNA secondary to an inherited defect in mismatch repair mechanisms. […] Other genetic mutations continue to be identified, which account for a smaller percentage of HNPCC cancers, but remain important for the diagnosis and screening of patients and their families.

• #95 History and Pathogenesis of Lynch Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3423881/

  Cell cycle check point kinase 2 (CHEK2) is yet another alternative mechanism for early-onset cancer with a Lynch phenotype. […] This finding has led to consideration of an alternative pathway to Lynch syndrome, not previously identified. […] The classic pathway for development of Lynch syndrome cancers is through the accumulation of mismatched bases in microsatellite areas of DNA secondary to an inherited defect in mismatch repair mechanisms. […] Other genetic mutations continue to be identified, which account for a smaller percentage of HNPCC cancers, but remain important for the diagnosis and screening of patients and their families.

• #96 An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms | OMICS International

  https://www.omicsonline.org/an-update-on-the-pathogenesis-of-lynch-syndrome-recently-described-novel-molecular-mechanisms-2161-069X-3-151.php?aid=21289

  Lynch syndrome, originally described in 1913 and previously known as hereditary nonpolyposis colorectal carcinoma syndrome, is the most common hereditary cancer syndrome. This syndrome is classically due to germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. […] Recently, EPCAM deletion, CHEK2 mutations, and germline MLH1 hypermethylation have been identified as alternative mutations that cause Lynch syndrome in mismatch repair-negative patients. This article reviews these novel mechanisms and mutations, their clinical significance, and the pathogenesis of these Lynch causing mutations. […] A subset of approximately 40% of patients with Lynch syndrome that meet clinical criteria and have a microsatellite instability-high colorectal cancer do not have an identifiable mutation in one of the four mismatch repair genes.

• #97 SciELO Brazil – Mismatch repair genes in Lynch syndrome: a review Mismatch repair genes in Lynch syndrome: a review

  https://www.scielo.br/j/spmj/a/KHmVWSq53tmSx6n3jznsB8n/

  For Lynch syndrome to be defined molecularly, a defect inherited in the mismatch repair genes needs to be demonstrated. […] Thus, germline mutations in at least one of the repair genes can be found in more than 80% of the individuals with Lynch syndrome. […] The main types of mutations found in these genes are missense, nonsense, frameshift and splice junction mutations, which can easily be detected by automatic sequencing. […] Despite much research on genetic abnormalities in the coding regions of the mismatch repair genes in Lynch syndrome cases, the genetic abnormalities in the promoter of these genes have been poorly investigated. […] Recent studies have been defining and characterizing germline mutations in the central area of the promoters of these genes. […] These results are indicative that mutations in MSH2 promoter are responsible for the initial tumor-forming process in a minority of Lynch syndrome cases. […] Studies have been demonstrating that hypermethylation of MLH1, also known as epimutation, is not limited to neoplastic cells. […] These results suggest that hypermethylation associated with silencing of MLH1 represents an alternative to the two-hit model.

• #98 Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications | European Journal of Human Genetics

  https://www.nature.com/articles/5201584

  However, because the sensitivity of mutational testing is low when predicated on these features, any measure that can be employed to increase the specificity of mutational testing without compromising sensitivity should be considered. […] The high percentage of this founder mutation among Lynch syndrome cases bears significant implications for cancer control. Testing for recurrent and founder mutations as a first step may considerably facilitate the molecular diagnosis of the disease in the appropriate populations. […] Cancer-related morbidity and mortality may be reduced significantly through highly targeted surveillance and management measures that are based on knowledge of the natural history and cardinal features of the Lynch syndrome.

Zobacz więcej