Materiały źródłowe

• #1 Familial Adenomatous Polyposis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/175377-overview

  Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. If left untreated, all patients with this syndrome will develop colon cancer by age 35-40 years. In addition, an increased risk exists for the development of other malignancies. […] The genetic defect in FAP is a germline mutation in the adenomatous polyposis coli (APC) gene. […] The APC gene is a tumor suppressor gene that is located on band 5q21. Its function is not completely understood but has been shown to play a part in metaphase chromosome alignment. Normal APC protein promotes apoptosis in colonic cells. Its most important function may be to sequester the growth stimulatory effects of b-catenin, a protein that transcriptionally activates growth-associated genes in conjunction with tissue-coding factors. Mutations of the APC gene result in a truncated/nonfunctional protein.

• #2 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10056005/

  Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. […] The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. […] This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. […] Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways.

• #3 The genetic basis of colonic adenomatous polyposis syndromes | Hereditary Cancer in Clinical Practice | Full Text

  https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-017-0065-x

  Familial adenomatous polyposis (FAP) accounts for approximately 1% of all CRCs and is an autosomal dominantly inherited condition where affected individuals develop hundreds to thousands of adenomas (polyposis) throughout the colon and rectum at unusually young ages. The disease is due to mutations in the adenomatous polyposis coli (APC) gene. If left untreated (if the colon is not removed), one or more of these adenomas invariably become malignant with almost 100% penetrance. […] FAP is a result of germline mutations in APC. APC is a tumour suppressor gene that plays a central role in the Wnt signalling pathway. […] Mutations in APC affect the ability of the cell to maintain normal growth and function, which results in cell overgrowth/adenoma formation. […] About 25% of people with FAP do not have any family history of disease and harbour a de novo mutation in APC without any clinical or genetic evidence of FAP in the family.

• #4 Familial Adenomatous Polyposis: Alarming Symptoms, Causes, Types, Diagnosis and Treatment – OncoDaily

  https://oncodaily.com/oncolibrary/cancer-types/familial-adenomatous-polyposis

  Familial adenomatous polyposis (FAP) is a hereditary disorder caused by a mutation in the APC gene, leading to the development of hundreds to thousands of colorectal polyps. […] FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. This mutation leads to uncontrolled cell growth, resulting in the formation of numerous polyps in the colon and rectum. […] The majority of FAP cases are inherited, but around 25% of cases result from a de novo mutation. […] Classic Familial Adenomatous Polyposis (FAP) is a hereditary condition where individuals develop hundreds to thousands of polyps in the colon and rectum, typically during their teenage years. These polyps are benign at first but carry a nearly 100% risk of turning into colorectal cancer by age 35 if left untreated. […] Without intervention, FAP almost inevitably progresses to cancer, making timely management essential.

• #5 Familial Adenomatous Polyposis | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/21606

  Familial adenomatous polyposis (FAP) is an autosomal dominant polyposis syndrome characterized by varying degrees of penetrance. The primary genetic defect associated with this disorder is a germline mutation in the adenomatous polyposis coli (APC) gene. […] FAP results from mutations in the APC gene, a tumor suppressor gene located on chromosome 5, exhibiting autosomal dominant inheritance. Germline mutations, often involving nonsense mutations, typically lead to classic FAP. The extensive size of the APC gene results in variable genotypes and phenotypes. […] The APC gene acts as a tumor suppressor gene, essential for chromosome alignment during metaphase. The APC protein promotes apoptosis in colonic epithelial cells. Mutations in the APC protein disrupt apoptosis and facilitate uncontrolled cell growth, leading to adenoma development. The adenoma to carcinoma sequence is well documented, progressing sequentially, with APC inactivation as the initial step. Subsequent mutations in other oncogenes and tumor suppressor genes, such as KRAS and p53, induce dysplasia and eventual carcinoma. APC gene mutations are prevalent not only in familial cases but also in the majority of sporadic colorectal cancers.

• #6 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10056005/

  The APC gene was first discovered in the 1970s, and, in the following years, follow-up studies deeply analyzed its structure and function. […] It is located on chromosome 5, in the q21 region; it is a ubiquitous tumor-suppressor gene involved in the regulation of -catenin in all tissues as part of the WNT signaling pathway, as it prevents constant activation of -catenin that would bring uncontrolled cellular proliferation. […] In patients with FAP, a loss of function APC mutation will directly influence the WNT signaling pathway; when the proliferation signal mediated by WNT is absent, -catenin is phosphorylated, bound to the destruction complex, namely a protein assembly made up of APC, axin (a cytosolic scaffold protein), conductin (a protein that phosphorylates serine and threonine residues of centrosomes) and glycogen synthase kinase 3 b (GSK3b), and eventually degraded by proteasomes.

• #7 Familial Adenomatous Polyposis | Concise Medical Knowledge

  https://www.lecturio.com/concepts/familial-adenomatous-polyposis/

  Familial adenomatous polyposis (FAP) is an autosomal dominant inherited genetic disorder that presents with numerous adenomatous polyps. Familial adenomatous polyposis is the most common of the polyposis syndromes, which is a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract, associated with other extracolonic features. These syndromes are caused by mutations in specific genes associated with tumor suppression or cell cycle regulation. Pathogenic mutations in the tumor suppressor gene adenomatous polyposis coli (APC) in chromosome 5 on band 5q21: Often nonsense or frameshift mutations evolve into truncation of the APC protein, creating a nonfunctional protein. The APC gene exerts a tumor-suppression function that induces apoptosis. Dysfunctional APC protein prevents colonic cell apoptosis, allowing β-catenin protein to accumulate intracellularly, stimulating cell growth and uncontrolled growth of cells, leading to adenomatous polyps. Enough genetic events occur to allow the polyps to become malignant.

• #8 Familial Adenomatous Polyposis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/175377-overview

  The resultant loss of APC function prevents apoptosis and allows b-catenin to accumulate intracellularly and to stimulate cell growth with the consequent development of adenomas. As the clonal expansion of cells that lack APC function occurs, their rapid growth increases the possibility for other growth-advantageous genetic events to occur. This causes alterations in the expression of a variety of genes, thereby affecting the proliferation, differentiation, migration, and apoptosis of cells. […] Ultimately, enough genetic events transpire that allow the adenomatous polyps to become malignant in patients with FAP. This process is similar to that which occurs in sporadic adenomas. As a result, APC is considered the gatekeeper of colonic neoplasia. Its mutation/inactivation is the initial step in the development of colorectal cancer in patients with FAP.

• #9 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10056005/

  Therefore, -catenin is no longer destroyed and cells receive a proliferation signal; once stabilized, -catenin migrates to the nucleus, where it acts as a transcriptional activator: it provides an uncontrolled permanent mitogenic signal, through the interaction with DNA-binding proteins. […] The different functions altered in APC mutations may drive and promote CRC genesis. […] The process of tumorigenesis also in the case of FAP follows Knudsons two-hit hypothesis, with the inactivation of both APC alleles; in FAP the first hit is represented by the inherited germline mutation. […] Selective advantage was related to alterations in replication, segregation and survival, secondary to APC mutations acquired by the cells, initiates and drives tumorigenesis; further concomitant somatic mutations in other genes (i.e., KRAS, TP53) will follow as a consequence in a stepwise manner, accelerating the tumorigenic process along the adenoma to carcinoma sequence.

• #10 Familial Adenomatous Polyposis: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/175377-overview

  Germline (ie, inherited) mutations of the APC gene, as is the case with FAP, result in cells containing one mutated copy and one normal copy of the gene. Patients inherit one mutated APC allele from an affected parent, and adenomas develop as the second allele from the unaffected parent becomes mutated or lost. Consequently, every colonic epithelial cell in patients with FAP has one mutated APC allele. Inactivation of the remaining normal copy of the APC gene, by deletion or mutation, completely removes the tumor suppressive function of APC, thus initiating the growth of adenomatous polyps. Inactivation of the second APC allele occurs frequently in the colon, resulting in the development of numerous adenomas.

• #11 FAP : Molecular Pathogenesis

  https://www.webpathology.com/images/gastrointestinal/large-bowel/neoplastic-polyps/42620

  Familial adenomatous polyposis (FAP) is caused by germline loss-of-function mutations in the tumor suppressor gene APC (on 5q22.2) which are passed on to the offspring. […] Colonic adenomas develop when the second allele acquired from the unaffected parent is mutated or lost (second hit). […] One of more of the adenomas subsequently undergo malignant transformation following acquisition of additional mutations, such as activation of KRAS and disruption of p53. […] In FAP, the number of polyps and their time-frame to malignant transformation depends upon specific mutations within the APC gene. […] Mutations in APC gene are also found in 70% to 80% of non-hereditary colon cancers as well as sporadic adenomas.

• #12 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10056005/

  Somatic APC mutations are also found in sporadic CRC cases. […] The germline APC mutation, together with the progressive accumulation of mutations involving other oncogenes and tumor-suppressor genes, will cooperate to alter genomic stability. […] Such alterations give rise to chromosomal instability (CIN), a distinctive characteristic of cancers arising from APC mutations, as opposed to the other form of hereditary CRC with genetic instability such as microsatellite instability in Lynch syndrome. […] The progressive nature of this disease requires a constant need for endoscopic surveillance from late childhood or adolescence even after surgery, indicated when the disease is no longer manageable by endoscopic procedures due to the high burden of polyps, CRC or symptomatic polyps; moreover, patients also have to continuously monitor extra-intestinal disease manifestations.

• #13

  https://www.omim.org/entry/175100

  Boland et al. (1995) performed microallelotyping of many regions from individual colorectal tumors to determine the sequence and tempo of allelic loss at 5q, 17p, and 18q during neoplastic progression. No allelic losses were found in normal tissues surrounding colorectal neoplasms, but losses occurred abruptly on 5q at the transition from normal colonic epithelium to benign adenoma, and on 17p at the transition from adenoma to carcinoma, indicating an essential role for these losses in tumor progression. Allelic losses were uniform throughout extensively microdissected benign adenomas and carcinomas. However, substantial allelic heterogeneity was found in high-grade dysplasia, the transition lesion between adenoma and carcinoma. Boland et al. (1995) concluded that 5q (presumably APC) and 17p (presumably p53) are associated with abrupt waves of clonal neoplastic expansion.

• #14

  https://www.omim.org/entry/175100

  It is widely accepted that tumors are monoclonal in origin, arising from a mutation or series of mutations in a single cell and its descendants (Fialkow, 1979). Contradictory findings were reported by Novelli et al. (1996) who used direct in situ hybridization with Y chromosome probes to examine the clonal origin of colonic adenomas and uninvolved intestinal mucosa from an XO/XY mosaic individual with FAP. In this patient, the crypts of the small and large intestine were clonal, but at least 76% of the microadenomas were polyclonal in origin. Although other interpretations were considered, such as collision of separate tumors, Novelli et al. (1996) felt the results most strongly favored a true polyclonal nature of the polyps. […] By examining DNA replication errors in specific tumors, Homfray et al. (1998) found no evidence of mismatch repair defects occurring before APC mutations in the pathogenesis of sporadic colorectal tumors. The authors concluded that APC mutations, rather than genomic instability, are the initiating events in sporadic tumorigenesis.

• #15

  https://www.omim.org/entry/175100

  Shih et al. (2001) found that dysplastic cells at the tops of crypts of small colorectal adenomas contained APC alterations. In contrast, cell at the base of these same crypts did not contain APC alterations and were not clonally related to the transformed cells above. These findings implied that development of adenomatous polyps proceeds through a 'top-down’ mechanism. Genetically altered cells in the superficial portions of the mucosae spread laterally and downward to form new crypts that first connect to preexisting normal crypts and eventually replace them. […] In a review of pathology reports from 44 individuals with FAP, Crabtree et al. (2001) found a correlation between adenoma:crypt ratio and macroscopic adenoma counts (r = 0.82, p less than 0.001) within individuals. There was no apparent variation in polyp density within a single colon at the microscopic level. There was also no detectable age-related increase in macroscopic adenoma count between sibs over the age range at which colectomies had been performed. The authors concluded that variation in disease severity was likely to result from different rates of tumor initiation rather than from differences in progression from microadenomas to macroscopic adenomas. The apparent lack of association between adenoma number and age suggested that most tumors may be initiated relatively early in a patient’s life. […] Houlston et al. (2001) comprehensively reviewed mechanisms underlying phenotypic variability in individuals with FAP.

• #16 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://www.mdpi.com/1422-0067/24/6/5687

  Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. […] The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. […] Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways.

• #17 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://www.mdpi.com/1422-0067/24/6/5687

  Such alterations give rise to chromosomal instability (CIN), a distinctive characteristic of cancers arising from APC mutations, as opposed to the other form of hereditary CRC with genetic instability such as microsatellite instability in Lynch syndrome. […] Multiple and diffuse adenomas in different stages of development are the hallmark of FAP; novel studies analyzing the genomic and transcriptomic profile of these patients have shed some light on the cancerogenic process. […] The interaction between gut microbiota and the human host has recently been investigated due to its major role in development of colorectal polyps and progression to CRC, both in sporadic and hereditary settings, as well as its implication in the pathogenesis of other diseases not only restricted to the gastrointestinal tract.

• #18 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10056005/

  One of the most studied pathways involved is cyclooxygenase (COX), more specifically in the isoform COX-2, a key enzyme involved in arachidonic acid transformation in prostaglandins and a target of common non-steroidal anti-inflammatory drugs. […] The results obtained by both human and murine studies have pointed out a possible role for estrogen in cancer prevention, in both sporadic and high-risk individuals with hereditary CRC predisposition, and has also been proposed to be the basis of the gender-related difference in CRC risk seen in premenopausal women compared to age-matched men, which is abolished after the onset of menopause.

• #19 Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

  https://www.mdpi.com/1422-0067/24/6/5687

  The adenoma to carcinoma sequence could be deeply influenced by some species of bacteria that contribute in many ways to polyposis progression. […] The protective mechanism of estrogen in the adenoma to carcinoma sequence was investigated using ApcMin/+ mice models, which simulate the hereditary CRC pathway. […] The progressive nature of this disease requires a constant need for endoscopic surveillance from late childhood or adolescence even after surgery, indicated when the disease is no longer manageable by endoscopic procedures due to the high burden of polyps, CRC or symptomatic polyps; moreover, patients also have to continuously monitor extra-intestinal disease manifestations. […] Despite novel advances in the understanding of the molecular mechanisms here reviewed underlying the pathogenesis of FAP, the complete mechanisms are far from being defined.

• #20 The genetic basis of colonic adenomatous polyposis syndromes | Hereditary Cancer in Clinical Practice | Full Text

  https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-017-0065-x

  New methods that can screen genomic loci at great depths are revealing that patients that were thought to be APC mutation negative have pathogenic germline heterozygous APC mutations, APC promoter mutations, deep intronic mutations, complex genomic rearrangements, somatic mutations or APC mutation mosaicism. […] In families with FAP, considerable variability in disease expression is observed within and between families harbouring identical APC mutations and it has been shown that the greater the number of colorectal adenomas, the greater the risk of CRC. […] Genotype-phenotype correlations have been associated with the location of germline mutations within APC that are related to disease severity and the expression of extra-colonic disease. […] The phenotypic variation of APC Min mouse model of FAP reveal among different inbred strains the importance of modifier alleles. There is evidence to suggest that these phenotypic differences are caused by segregating modifier alleles that impact adenoma number.

• #21 Familial adenomatous polyposis (FAP)

  https://atlasgeneticsoncology.org/cancer-prone-disease/10012/familial-adenomatous-polyposis-(fap)

  Familial adenomatous polyposis (FAP) is caused by a highly heterogeneous spectrum of point mutations that represents a problem for molecular genetic diagnosis; but all the mutations are chain terminating and some correlations between the position of the mutation and the phenotypic consequences have been described: […] germline mutations between codons 1250 and 1464 are associated with profuse polyposis; […] an attenuated adenomatous polyposis coli (AAPC) is associated with mutations located very close to the 5-prime end of the APC gene; […] the extent of congenital hypertrophy of the retinal pigment epithelium (CHRPE) depends on the position of the protein-truncating mutation in APC; CHRPE lesions are almost always absent if the mutation occur before exon 9, but are consistently present if it occurs after this exon; […] patients with a mutation between codons 1445 and 1578 do not express CHRPE; however, these patients developed severe desmoid tumors.

• #22 The genetic basis of colonic adenomatous polyposis syndromes | Hereditary Cancer in Clinical Practice | Full Text

  https://hccpjournal.biomedcentral.com/articles/10.1186/s13053-017-0065-x

  Several studies suggest that low-penetrant susceptibility genes may play an important role in the development of sporadic CRC. There is evidence to show that the variation in FAP severity (which have been shown to be independent of APC mutations and most likely the action of modifier alleles), is expected to result in different rates of adenoma number rather than differences in tumour progression. […] As described above there is plenty of evidence from animal models for the existence of FAP modifiers and knowledge of modifier genes will contribute to better prophylactic measures for FAP patients.

• #23 Familial adenomatous polyposis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/familial-adenomatous-polyposis/

  Familial adenomatous polyposis (FAP) is an inherited disorder characterized by cancer of the large intestine (colon) and rectum. […] Mutations in the APC gene cause both classic and attenuated familial adenomatous polyposis. These mutations affect the ability of the cell to maintain normal growth and function. Cell overgrowth resulting from mutations in the APC gene leads to the colon polyps seen in familial adenomatous polyposis. […] Mutations in the MUTYH gene cause autosomal recessive familial adenomatous polyposis (also called MUTYH-associated polyposis). Mutations in this gene prevent cells from correcting errors that are made when DNA is copied (DNA replication) in preparation for cell division. As these errors build up in a person’s DNA, the likelihood of cell overgrowth increases, leading to colon polyps and the possibility of colon cancer.

• #24

  https://www.omim.org/entry/175100

  Genetic Heterogeneity of Familial Adenomatous Polyposis […] See also autosomal recessive FAP2 (608456), caused by mutation in the MUTYH gene (604933) on chromosome 1p34; autosomal recessive FAP3 (616415), caused by mutation in the NTHL1 gene (602656) on chromosome 16p13; and autosomal recessive FAP4 (617100), caused by mutation in the MSH3 gene (600887) on chromosome 5q11. […] Hsu et al. (1983) found that the polyps of Gardner syndrome are multiclonal in origin, as are the tumors in neurofibromatosis (NF1; 162200) and trichoepithelioma (see 601606). Rasheed et al. (1983) demonstrated that skin fibroblasts from patients with Gardner syndrome and familial polyposis coli showed increased susceptibility to retrovirus-induced transformation and chromosomal aneuploidy. Chen et al. (1989) concluded that the in vitro life span of cultured skin fibroblasts from individuals with FPC is markedly extended when compared with that of normal individuals.

• #25 Familial adenomatous polyposis – Wikipedia

  https://en.wikipedia.org/wiki/Familial_adenomatous_polyposis

  Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. […] The root cause of FAP is understood to be a genetic mutationa change in the body’s tumour suppressor genes that prevent development of tumours. […] A flaw in the APC gene means APC is not as effective as it should be, and over time it is likely that some cells that should have been controlled by APC will not be, and will instead continue to develop and become cancerous. […] Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. […] Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer. […] Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder.

• #26 Prof Fuchou Tang’s and Prof Wei Fu’s groups uncovered pathogenesis of familial adenomatous polyposis (FAP) – BIOPIC网站英文版

  https://biopic.pku.edu.cn/en/newscenter/scientificupdates/511527.htm

  Prof Fuchou Tangs and Prof Wei Fus groups uncovered pathogenesis of familial adenomatous polyposis (FAP) […] Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome and is caused by inherited mutations in adenomatous polyposis coli (APC). […] The main findings of the paper are as follows: […] Spatially separated tumors can originate from the same cancer-primed cell in patients with FAP, indicating that the pathogenic events may happen long before the appearance of clinically identifiable adenomas, even in a macroscopically normal epithelium. […] This phenomenon emphasizes that pathogenic events may occur long before the appearance of clinically identifiable adenomas, even in macroscopically normal epithelium. […] Enhanced metabolic processes and proliferative activity in the normal epithelium of patients with FAP.

• #27 Prof Fuchou Tang’s and Prof Wei Fu’s groups uncovered pathogenesis of familial adenomatous polyposis (FAP) – BIOPIC网站英文版

  https://biopic.pku.edu.cn/en/newscenter/scientificupdates/511527.htm

  The metabolic signature of cancer has already been established in precancerous adenomas. […] In summary, we provided the first picture of the transcriptomic landscape of colorectal carcinogenesis in patients with FAP. The transcriptome dynamics during carcinogenesis were comprehensively investigated. In addition, we found that field cancerization occurs in patients with FAP. These findings will advance our understanding of the pathogenesis of CRC.

• #28 Multiomic analysis of familial adenomatous polyposis reveals molecular pathways associated with early tumorigenesis | Nature Cancer

  https://www.nature.com/articles/s43018-024-00831-z

  This rich open-access multiomic, multisample dataset also provides a valuable scientific resource to the community, complementing the existing datasets on sporadic CRCs. […] To understand the molecular pathways activated during the early stages of polyp formation and cancer progression, we performed deep multiomic profiling of histologically normal mucosa, benign polyps and dysplastic polyps. […] The transition of polyps to dysplasia was characterized by proteomic and transcriptomic alterations that were predominantly downregulated; functional enrichment was nearly entirely composed of downregulated pathways. […] Arachidonic acid signaling was also upregulated early during polyp formation, contributing to inflammation. […] While aspirin and NSAIDs are commonly used as prophylactic treatment for persons with FAP, the mechanism of action and optimal timing of this intervention are not known. […] This rich multimodal dataset illuminates the steps involved in precancer formation and transition to malignancy at unprecedented resolution and should serve as a valuable resource for the community.

• #29

  https://link.springer.com/article/10.1007/s10689-020-00189-y

  Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome characterized by colorectal adenomas and a near 100% lifetime risk of colorectal cancer (CRC). […] Substantial research has investigated chemoprevention medications in an aim to prevent disease progression, postponing the need for colectomy and temporizing the development of extracolonic disease. […] Substantial preclinical literature exists linking the molecular target of rapamycin (mTOR) pathway to FAP. […] A single case report of rapamycin, an mTOR inhibitor, used as chemoprevention in FAP patients exists, but no formal clinical studies have been conducted. […] New agents targeting novel pathways in FAP are needed. […] Here, we review the prior literature on chemoprevention in FAP, discuss the rationale for rapamycin in FAP, and outline a proposed clinical trial testing rapamycin as a chemoprevention agent in patients with FAP.

• #30 Managing familial adenomatous polyposis (FAP): new approaches | MD Anderson Cancer Center

  https://www.mdanderson.org/cancerwise/new-approaches-to-managing-familial-adenomatous-polyposis–fap.h00-159537378.html

  Even when the colon is removed, polyps can still form in the remaining gastrointestinal tissue. Many patients later develop cancer in their duodenum, which is the first part of the small intestine. […] The anti-inflammatory drug sulindac can serve as a chemoprevention therapy as an alternative approach to managing polyps in the duodenum. […] One clinical trial is studying obeticholic acid (Ocaliva), an FDA-approved oral drug that acts as a synthetic bile acid to stops pathways of intestinal stem cells. Because the medication is already approved for patients with primary biliary cirrhosis, theres a good amount of data proving the safety of the drug and its effects, Vilar-Sanchez says. Along with his team, hes investigating if obeticholic acid can serve as a chemoprevention therapy to slow or halt the development of polyps in the duodenum of patients with FAP who have received a colectomy.

• #31 Familial Adenomatous Polyposis (FAP) | Boston Children’s Hospital

  https://www.childrenshospital.org/conditions/familial-adenomatous-polyposis

  The most important treatment for FAP is the early removal of the entire colon (prophylactic colectomy) to prevent the development of cancer. The timing of surgery is based on the patients age or other high-risk factors, including family history, polyp number, and pre-malignant changes in the polyps. […] There is no cure for FAP. Treatment is directed to reduce complications, such as cancer, abdominal pain, bowel obstruction, and GI bleeding.

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