Materiały źródłowe

• #1 Leiomyosarcoma – Wikipedia

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

  A leiomyosarcoma (LMS) is a rare malignant (cancerous) smooth muscle tumor. […] Just as it is not known what truly causes most sarcomas, LMSs have similarly complex karyotypes and it is suggested that because of the complexity, genomic instability might be the cause. […] Uterine leiomyosarcomas come from the smooth muscle in the muscle layer of the uterus. […] At most other primary sites leiomyosarcomas appear to grow from the muscle layer of a blood vessel (the tunica media). […] The tumors are usually hemorrhagic and soft and microscopically marked by pleomorphism, abundant abnormal mitotic figures, and coagulative tumor cell necrosis.

• #2 Location, Location, Location: Approaches to Retroperitoneal Vascular Leiomyosarcoma

  https://www.cancernetwork.com/view/location-location-location-approaches-retroperitoneal-vascular-leiomyosarcoma

  Leiomyosarcoma, one of the most common soft tissue sarcomas, can occur anywhere in the body, but it is frequently found in the abdomen and retroperitoneum. […] Leiomyosarcomas, a subset of soft tissue sarcomas, are malignant smooth muscle neoplasms that account for approximately 5% to 10% of all sarcomas. Natural history is dependent on the anatomic location in which they arise. […] Leiomyosarcomas arising in the middle portion of the IVC (ie, infrahepatic, suprarenal) are the most frequent at about 40%, and symptoms may include a palpable abdominal mass, abdominal or visceral pain, and bilateral lower extremity edema. […] Vascular leiomyosarcomas are derived from smooth muscle cells within the medial layer of blood vessels. […] Leiomyosarcomas originating from the IVC account for approximately 0.5% of soft tissue sarcomas; about 300 of these tumors have been reported in this location in the literature.

• #3 Leiomyosarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551667/

  Leiomyosarcomas are primarily associated with RB1 and PTEN tumor suppressor gene mutations. RB1 gene mutations are observed in 90% of patients. The cytogenetic and molecular changes in leiomyosarcoma are inconsistent, contributing to its highly heterogeneous nature. More recent data from The Cancer Genome Atlas revealed that leiomyosarcoma, like other STSs, is associated with a lower tumor mutational burden compared to other types of cancers. […] Leiomyosarcoma is a tumor with complex and unbalanced karyotypes characterized by severe genomic instability, which results in multiple genetic aberrations. As a result, leiomyosarcoma is considered moderately sensitive to chemotherapy. […] Leiomyosarcoma staging is according to the organ of origin. Uterine leiomyosarcoma staging follows the Federation of Gynecology and Obstetrics (FIGO) staging system. According to the American Joint Committee of Cancer (AJCC) staging, an extrauterine leiomyosarcoma gets staged. However, the 8th edition of AJCC has resolved a long-standing variability in STS staging. In the latest edition, AJCC has provided a separate staging system for STS of the retroperitoneum, head or neck region, and extremities or trunk region.

• #4 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. […] Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. […] The karyotype of LMS is genomically complex, with multiple genes that are frequently altered to varying degrees and no pathognomonic chromosomic alteration. Overall, LMS has a lower tumor mutational burden (median of 2.61 mutations/Mb) and fewer somatic copy number alterations (SCNAs) than other complex genomic sarcomas.

• #5 Leiomyosarcoma | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/24180

  Leiomyosarcomas are primarily associated with RB1 and PTEN tumor suppressor gene mutations. RB1 gene mutations are observed in 90% of patients. The cytogenetic and molecular changes in leiomyosarcoma are inconsistent, contributing to its highly heterogeneous nature. More recent data from The Cancer Genome Atlas revealed that leiomyosarcoma, like other STSs, is associated with a lower tumor mutational burden compared to other types of cancers. […] Although there are no definite causative factors for leiomyosarcoma, certain risk factors have been associated with developing STSs, including leiomyosarcoma. The significant risk factor for STS is a history of radiation exposure or radiotherapy, particularly at a young age. STSs may also be part of genetic syndromes, such as retinoblastoma (due to RB1 gene deletion) and Li-Fraumeni syndrome (caused by a mutation in the TP53 gene).

• #6 Leiomyosarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/leiomyosarcoma/

  Cytogenetic, molecular cytogenetic, and next-generation sequencing studies show that LMSs display extensive genomic instability, including chromothripsis and whole-genome duplication in subsets of cases. […] Recurrent DNA copy-number alterations include losses involving tumor suppressors PTEN (10q23.31), RB1 (13q14.2), and TP53 (17p13.1), as well as amplification of MYOCD at 17p12, which encodes a smooth muscle–specific transcriptional coactivator. […] Whole-exome/genome and RNA sequencing studies have demonstrated that LMSs are characterized by a modest burden of somatic mutations and substantial mutational heterogeneity. […] TP53 is mutated in as many as 50% of sporadic LMSs; approximately 90% of samples present with biallelic TP53 inactivation through mutations, deletions, chromosomal rearrangements, or protein-damaging microalterations.

• #7 Pathology Outlines – Leiomyosarcoma

  https://www.pathologyoutlines.com/topic/uteruslms.html

  Rare, malignant mesenchymal tumor derived from myometrial smooth muscle. […] Derived from smooth muscle. […] Vast array of associated cytogenetic abnormalities but none are consistent or diagnostic. […] Most frequently mutated genes: TP53 (~30%), ATRX (~25%) and MED12 (~20%). […] No specific diagnostic / pathognomonic molecular alterations. […] Substantial mutational heterogeneity, widespread DNA copy number alterations including chromothripsis and frequent whole genome duplication. […] Hallmarks of „BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements and enrichment of specific mutational signatures. […] Alternative telomere lengthening (78%). […] Somatic mutations: TP53 (30 – 60%), ATRX (24 – 30%), RB1 (27 – 61%), MED12 (~20%), PTEN (~31 – 57%). […] C-MYC (18%) and TERT (26%) amplifications. […] NR4A3::PGR fusion or PGR rearrangements in 35% of epithelioid leiomyosarcomas. […] PLAG1 rearrangements in ~25% of myxoid leiomyosarcomas.

• #8 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. […] Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. […] The karyotype of LMS is genomically complex, with multiple genes that are frequently altered to varying degrees and no pathognomonic chromosomic alteration. Overall, LMS has a lower tumor mutational burden (median of 2.61 mutations/Mb) and fewer somatic copy number alterations (SCNAs) than other complex genomic sarcomas.

• #9 Leiomyosarcoma | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/24180

  Leiomyosarcomas are primarily associated with RB1 and PTEN tumor suppressor gene mutations. RB1 gene mutations are observed in 90% of patients. The cytogenetic and molecular changes in leiomyosarcoma are inconsistent, contributing to its highly heterogeneous nature. More recent data from The Cancer Genome Atlas revealed that leiomyosarcoma, like other STSs, is associated with a lower tumor mutational burden compared to other types of cancers. […] Although there are no definite causative factors for leiomyosarcoma, certain risk factors have been associated with developing STSs, including leiomyosarcoma. The significant risk factor for STS is a history of radiation exposure or radiotherapy, particularly at a young age. STSs may also be part of genetic syndromes, such as retinoblastoma (due to RB1 gene deletion) and Li-Fraumeni syndrome (caused by a mutation in the TP53 gene).

• #10 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  We have shown TP53 and RB1 inactivation in 90% of LMS, and TP53 and RB1 inactivating germline mutations are initiating events in LMS. […] Project 1 seeks to develop therapies that maximize intrinsic LMS genotoxic stress by targeting the key DNA damage response enzyme, DNA-PK. […] A genome-wide shRNA long-term screen identified genes with essential roles in early-passage LMS lines. […] These observations are the rationale for the overarching Project 1 hypothesis, which is that the intrinsic CIN in advanced LMS is a vulnerability that can be exploited, using doxorubicin coupled with targeted inhibitors, particularly DNA-PK inhibitors. […] Project 2 focuses on studying the genetic epidemiology of LMS defining the risk for cancer in families with cancer predisposition syndromes such as Li-Fraumeni Syndrome, as well as the general population by evaluating the largest ever cohort of LMS patients.

• #11 Pathology Outlines – Leiomyosarcoma

  https://www.pathologyoutlines.com/topic/uteruslms.html

  Rare, malignant mesenchymal tumor derived from myometrial smooth muscle. […] Derived from smooth muscle. […] Vast array of associated cytogenetic abnormalities but none are consistent or diagnostic. […] Most frequently mutated genes: TP53 (~30%), ATRX (~25%) and MED12 (~20%). […] No specific diagnostic / pathognomonic molecular alterations. […] Substantial mutational heterogeneity, widespread DNA copy number alterations including chromothripsis and frequent whole genome duplication. […] Hallmarks of „BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements and enrichment of specific mutational signatures. […] Alternative telomere lengthening (78%). […] Somatic mutations: TP53 (30 – 60%), ATRX (24 – 30%), RB1 (27 – 61%), MED12 (~20%), PTEN (~31 – 57%). […] C-MYC (18%) and TERT (26%) amplifications. […] NR4A3::PGR fusion or PGR rearrangements in 35% of epithelioid leiomyosarcomas. […] PLAG1 rearrangements in ~25% of myxoid leiomyosarcomas.

• #12 Leiomyosarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/leiomyosarcoma/

  Cytogenetic, molecular cytogenetic, and next-generation sequencing studies show that LMSs display extensive genomic instability, including chromothripsis and whole-genome duplication in subsets of cases. […] Recurrent DNA copy-number alterations include losses involving tumor suppressors PTEN (10q23.31), RB1 (13q14.2), and TP53 (17p13.1), as well as amplification of MYOCD at 17p12, which encodes a smooth muscle–specific transcriptional coactivator. […] Whole-exome/genome and RNA sequencing studies have demonstrated that LMSs are characterized by a modest burden of somatic mutations and substantial mutational heterogeneity. […] TP53 is mutated in as many as 50% of sporadic LMSs; approximately 90% of samples present with biallelic TP53 inactivation through mutations, deletions, chromosomal rearrangements, or protein-damaging microalterations.

• #13 Leiomyosarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/leiomyosarcoma/

  Similarly, the function of RB1 is disrupted in nearly all cases of soft tissue LMS by diverse mechanisms that either target RB1 itself or result in altered expression of CDKN2A, CCND1, CCND2, or CDK4. […] Potentially deleterious ATRX alterations have been observed in 16–49% of cases and probably contribute to the high prevalence of alternative lengthening of telomeres in LMS. […] ALK rearrangements have been identified in a small subset of LMSs (9 of 377 cases; 2.4%) arising in males and females (soft tissue and uterine), imparting potential for clinically actionable opportunities. […] Gene expression studies suggest that there are multiple subgroups of LMS, including a muscle-enriched subtype and less-differentiated groupings, with indications of differing frequencies of specific genomic changes and varying prognoses.

• #14 Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12 | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005850

  Immunohistochemical analysis including 50 ULMSs confirmed altered expression in the majority of tumors, highlighting the role of TP53 in ULMS development. […] Loss of ATRX expression has been reported in leiomyosarcomas of various sites and a recent meeting abstract on ULMSs reported genomic alterations of this gene in 32% (8/25) of the studied tumors, supporting our findings. […] Importantly, ALT was recently suggested to render cancer cells hypersensitive to ATR inhibitors. […] While MED12 mutations are the most common alterations in benign conventional leiomyomas, TP53 or ATRX mutations have not been observed in these tumors. […] Specifically, identification of inactivating ATRX mutations and their association with the ALT phenotype in the substantial proportion of tumors may be translatable into clinical practice should the suggested effect of ATR inhibitors prove effective.

• #15 Pathology Outlines – Leiomyosarcoma

  https://www.pathologyoutlines.com/topic/uteruslms.html

  Rare, malignant mesenchymal tumor derived from myometrial smooth muscle. […] Derived from smooth muscle. […] Vast array of associated cytogenetic abnormalities but none are consistent or diagnostic. […] Most frequently mutated genes: TP53 (~30%), ATRX (~25%) and MED12 (~20%). […] No specific diagnostic / pathognomonic molecular alterations. […] Substantial mutational heterogeneity, widespread DNA copy number alterations including chromothripsis and frequent whole genome duplication. […] Hallmarks of „BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements and enrichment of specific mutational signatures. […] Alternative telomere lengthening (78%). […] Somatic mutations: TP53 (30 – 60%), ATRX (24 – 30%), RB1 (27 – 61%), MED12 (~20%), PTEN (~31 – 57%). […] C-MYC (18%) and TERT (26%) amplifications. […] NR4A3::PGR fusion or PGR rearrangements in 35% of epithelioid leiomyosarcomas. […] PLAG1 rearrangements in ~25% of myxoid leiomyosarcomas.

• #16 MED12 mutations in leiomyosarcoma and extrauterine leiomyoma | Modern Pathology

  https://www.nature.com/articles/modpathol2012203

  Leiomyoma and leiomyosarcoma share morphological features and smooth muscle differentiation, and both arise most frequently within the uterine corpus of middle-aged women. However, they are considered biologically unrelated tumors due to their disparate clinical, cytogenetic, and molecular features. MED12, the mediator complex subunit 12 gene, has been recently implicated as an oncogene in as many as 70% of sporadic uterine leiomyoma. […] In the present study, we show MED12 hotspot exon 2 mutations in extrauterine leiomyoma (3 of 19 cases) and in leiomyosarcoma (3 of 13 uterine cases). […] These findings indicate that MED12 has oncogenic roles in a broad range of smooth muscle neoplasia, including tumors arising in extrauterine locations. […] In these studies, we also determined whether MED12 expression is dysregulated in smooth muscle neoplasia compared with a normal myometrium control. These studies demonstrate that MED12 mutations are the first known oncogenic mechanism shared by uterine and extrauterine leiomyoma and uterine leiomyosarcoma.

• #17 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  Leiomyosarcoma is a rare cancer. […] Our goal is to improve the knowledge regarding leiomyosarcoma (LMS) genetics, biology, and therapeutic approaches to rationally develop novel and more effective therapies including combinations of different agents targeting different pathways to exploit unique vulnerabilities. […] Project 1 aims to identify and exploit genomic vulnerabilities in LMS targeting the dependency on the non-homologous end joining DNA repair pathway and the associated enzyme DNA-activated protein kinase (DNA-PK). […] We have shown that LMS are highly dependent on the NHEJ protein, DNA-activated protein kinase (DNA-PK). […] TP53 inactivation results in tolerance to aneuploidy and double-strand DNA damage, and concurrent RB1 inactivation exacerbates these defects, hastening acquisition of tumor suppressor gene mutations.

• #18 Leiomyosarcoma – NCI

  https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-soft-tissue-tumors/leiomyosarcoma

  It is not known what causes LMS to form. Scientists are always working to understand how cancer forms, but it can be hard to prove. […] We do know that some genetic conditions are associated with LMS. These genetic conditions include hereditary retinoblastoma, Li-Fraumeni syndrome, neurofibromatosis type 1, tuberous sclerosis, nevoid basal cell carcinoma syndrome, Gardner syndrome, and Werner syndrome.

• #19 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The Cancer Genome Atlas project confirmed mutations and deletions in RB1, p53, and PTEN in all LMS, including uLMSs, and an overall low mutational burden in sarcomas compared to other tumors. […] Uterine sarcoma patients in a relatively large cohort sample (n = 145) showed frequently harbored pathogenic alterations in HR-DNA damage repair (DDR)-related genes. […] Studies reveal that LMS harbors defects in components of the HR repair pathways and is sensitive to treatments that induce double-stranded breaks or replication fork arrest. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al.

• #20 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The Cancer Genome Atlas project confirmed mutations and deletions in RB1, p53, and PTEN in all LMS, including uLMSs, and an overall low mutational burden in sarcomas compared to other tumors. […] Uterine sarcoma patients in a relatively large cohort sample (n = 145) showed frequently harbored pathogenic alterations in HR-DNA damage repair (DDR)-related genes. […] Studies reveal that LMS harbors defects in components of the HR repair pathways and is sensitive to treatments that induce double-stranded breaks or replication fork arrest. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al.

• #21 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11240800/

  Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. […] Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. […] In this review article, we provide the current state of knowledge by summarizing and discussing the cellular and molecular mechanisms underlying the regulation and emerging role of genetic, epigenetic, and biological pathways in the pathogenesis of uLMS. […] Evidence suggests that uLMS can arise de novo or secondary to malignant degeneration of an LM. uLMS is a malignant mesenchymal neoplasm that arises from the myometrium of the uterus. […] No single driving mutation has been identified for uLMS, but some potential driving mutations have been reported. […] Uterine sarcoma patients in a relatively large cohort sample (n = 145) showed frequently harbored pathogenic alterations in HR-DNA damage repair (DDR)-related genes.

• #22 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  Both uLMS and ST-LMS demonstrate fewer SCNAs than more immune-sensitive complex sarcomas, such as UPS. […] The presence of ongoing DNA damage and deficient DNA damage repair mechanisms has been observed to foster inflammatory signaling that results in intratumoral influx of immunosuppressive cells, particularly myeloid-derived suppressor cells and tumor-associated macrophages (TAMs). […] The administration of PARP inhibitors has been observed to produce a more robust infiltration of cytotoxic CD8+ T cells. This has been hypothesized to be a result of cytosolic DNA formation caused by double-strand DNA breaks generated by PARP inhibition, which results in increased secretion of proinflammatory cytokines IL-2, TNFα, and IFNγ, leading to subsequent CD8+ T-cell activation. […] The immune landscape of both ST-LMS and uLMS is characterized by a lower density of intratumoral immune cell infiltration than other sarcoma histologies with complex karyotypes.

• #23 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The Cancer Genome Atlas project confirmed mutations and deletions in RB1, p53, and PTEN in all LMS, including uLMSs, and an overall low mutational burden in sarcomas compared to other tumors. […] Uterine sarcoma patients in a relatively large cohort sample (n = 145) showed frequently harbored pathogenic alterations in HR-DNA damage repair (DDR)-related genes. […] Studies reveal that LMS harbors defects in components of the HR repair pathways and is sensitive to treatments that induce double-stranded breaks or replication fork arrest. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al.

• #24 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11240800/

  uLMS typically has complex karyotypes, aneuploids, and many other genetic defects suggesting dysfunction of DNA repair pathways, including HR in LMS. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al. […] The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] These findings reveal that divergent pathways participate in the uLMS pathogenesis, reflecting the complex mechanisms underlying this aggressive tumor development. […] Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #25 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11240800/

  uLMS typically has complex karyotypes, aneuploids, and many other genetic defects suggesting dysfunction of DNA repair pathways, including HR in LMS. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al. […] The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] These findings reveal that divergent pathways participate in the uLMS pathogenesis, reflecting the complex mechanisms underlying this aggressive tumor development. […] Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #26 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] The protein kinases are classified into two main families based on the ability to phosphorylate either serine and threonine or tyrosine residues. […] The role and regulatory mechanism of histone modifications have been extensively investigated in uLMS. […] These findings suggest that multiple epigenetic mechanisms are involved in the pathogenesis of uLMS. Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #27 Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma | Anticancer Research

  https://ar.iiarjournals.org/content/36/10/4997

  Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. […] Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. […] Here, we reviewed human uterine LMS for genetic mutations in the IFN signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/1i promoter regions. […] The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

• #28 Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma | Anticancer Research

  https://ar.iiarjournals.org/content/36/10/4997

  Therefore, defective PSMB9/1i expression is likely to be one of the risk factors in the development of human uterine LMS, as it is in PSMB9/1i-deficient mice. […] The defect was localized to JAK1 activation, which acts upstream in the IFN signalling pathway, since IFN treatment did not strongly induce JAK1 kinase activity in the SKN human uterine LMS cell line. […] Overall, nearly 43.5% (10/23) of human uterine LMS tissues had serious mutations in the ATP-binding region or kinase-specific active site of JAK1. […] The discovery of these mutational defects of a key cell-signalling pathway may be an important step in the understanding of the pathogenesis of human uterine LMS, in addition to our own research showing that somatic mutations of JAK1 correlate to the development of human uterine LMS.

• #29 Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma | Anticancer Research

  https://ar.iiarjournals.org/content/36/10/4997

  Therefore, defective PSMB9/1i expression is likely to be one of the risk factors in the development of human uterine LMS, as it is in PSMB9/1i-deficient mice. […] The defect was localized to JAK1 activation, which acts upstream in the IFN signalling pathway, since IFN treatment did not strongly induce JAK1 kinase activity in the SKN human uterine LMS cell line. […] Overall, nearly 43.5% (10/23) of human uterine LMS tissues had serious mutations in the ATP-binding region or kinase-specific active site of JAK1. […] The discovery of these mutational defects of a key cell-signalling pathway may be an important step in the understanding of the pathogenesis of human uterine LMS, in addition to our own research showing that somatic mutations of JAK1 correlate to the development of human uterine LMS.

• #30 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] The protein kinases are classified into two main families based on the ability to phosphorylate either serine and threonine or tyrosine residues. […] The role and regulatory mechanism of histone modifications have been extensively investigated in uLMS. […] These findings suggest that multiple epigenetic mechanisms are involved in the pathogenesis of uLMS. Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #31 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  Leiomyosarcoma is a rare cancer. […] Our goal is to improve the knowledge regarding leiomyosarcoma (LMS) genetics, biology, and therapeutic approaches to rationally develop novel and more effective therapies including combinations of different agents targeting different pathways to exploit unique vulnerabilities. […] Project 1 aims to identify and exploit genomic vulnerabilities in LMS targeting the dependency on the non-homologous end joining DNA repair pathway and the associated enzyme DNA-activated protein kinase (DNA-PK). […] We have shown that LMS are highly dependent on the NHEJ protein, DNA-activated protein kinase (DNA-PK). […] TP53 inactivation results in tolerance to aneuploidy and double-strand DNA damage, and concurrent RB1 inactivation exacerbates these defects, hastening acquisition of tumor suppressor gene mutations.

• #32 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  We have shown TP53 and RB1 inactivation in 90% of LMS, and TP53 and RB1 inactivating germline mutations are initiating events in LMS. […] Project 1 seeks to develop therapies that maximize intrinsic LMS genotoxic stress by targeting the key DNA damage response enzyme, DNA-PK. […] A genome-wide shRNA long-term screen identified genes with essential roles in early-passage LMS lines. […] These observations are the rationale for the overarching Project 1 hypothesis, which is that the intrinsic CIN in advanced LMS is a vulnerability that can be exploited, using doxorubicin coupled with targeted inhibitors, particularly DNA-PK inhibitors. […] Project 2 focuses on studying the genetic epidemiology of LMS defining the risk for cancer in families with cancer predisposition syndromes such as Li-Fraumeni Syndrome, as well as the general population by evaluating the largest ever cohort of LMS patients.

• #33 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] The protein kinases are classified into two main families based on the ability to phosphorylate either serine and threonine or tyrosine residues. […] The role and regulatory mechanism of histone modifications have been extensively investigated in uLMS. […] These findings suggest that multiple epigenetic mechanisms are involved in the pathogenesis of uLMS. Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #34 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://ouci.dntb.gov.ua/en/works/lDpBXoYl/

  Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. […] Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. […] The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis.

• #35 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://ouci.dntb.gov.ua/en/works/lDpBXoYl/

  Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. […] Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. […] The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis.

• #36 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] The protein kinases are classified into two main families based on the ability to phosphorylate either serine and threonine or tyrosine residues. […] The role and regulatory mechanism of histone modifications have been extensively investigated in uLMS. […] These findings suggest that multiple epigenetic mechanisms are involved in the pathogenesis of uLMS. Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #37 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11240800/

  uLMS typically has complex karyotypes, aneuploids, and many other genetic defects suggesting dysfunction of DNA repair pathways, including HR in LMS. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al. […] The regulation of the HH signaling pathway in LMS has been correlated with the expression of the transcription factor NKX6-1. […] These findings reveal that divergent pathways participate in the uLMS pathogenesis, reflecting the complex mechanisms underlying this aggressive tumor development. […] Therefore, targeted inhibition of epigenetic modulators may provide a promising and novel strategy for treating patients with this aggressive disease.

• #38 Epstein-Barr Virus-Positive Leiomyosarcoma in Immunocompetent Patients – Turkish Journal of Pathology

  https://turkjpath.org/text.php?id=2038

  EBV is involved in the pathogenesis of various tumors: 1) carcinomas, either prevalently such as nasopharyngeal carcinoma, or only certain subsets such as gastric carcinomas; 2) a wide range of lymphoproliferative disorders such as Burkitt lymphoma, Hodgkin lymphoma, and nasal type T/NK cell lymphoma to name a few; 3) some rare tumors such as Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) and inflammatory pseudotumor-like follicular dendritic cell tumor (IMT-FDCT). […] The pathogenesis and latency type of EBV-SMT is not well-known. MYC overexpression and activation of the mTOR/ Akt pathway are considered the main events in EBV-derived smooth muscle proliferation. […] The complete absence of LMP1 in all presented cases suggests that type I latency might be involved in EBV-SMT and EBV-positive LMS. However, previously reported del-LMP1 variant and EBNA2 expressions or a possible LMP2 might also be involved in these tumors, suggesting type II or more likely type III latency similar to post-transplant lymphoproliferative disorders.

• #39 Epstein-Barr Virus-Positive Leiomyosarcoma in Immunocompetent Patients – Turkish Journal of Pathology

  https://turkjpath.org/text.php?id=2038

  EBV is involved in the pathogenesis of various tumors: 1) carcinomas, either prevalently such as nasopharyngeal carcinoma, or only certain subsets such as gastric carcinomas; 2) a wide range of lymphoproliferative disorders such as Burkitt lymphoma, Hodgkin lymphoma, and nasal type T/NK cell lymphoma to name a few; 3) some rare tumors such as Epstein-Barr virus-associated smooth muscle tumor (EBV-SMT) and inflammatory pseudotumor-like follicular dendritic cell tumor (IMT-FDCT). […] The pathogenesis and latency type of EBV-SMT is not well-known. MYC overexpression and activation of the mTOR/ Akt pathway are considered the main events in EBV-derived smooth muscle proliferation. […] The complete absence of LMP1 in all presented cases suggests that type I latency might be involved in EBV-SMT and EBV-positive LMS. However, previously reported del-LMP1 variant and EBNA2 expressions or a possible LMP2 might also be involved in these tumors, suggesting type II or more likely type III latency similar to post-transplant lymphoproliferative disorders.

• #40 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. They have a poor prognosis with high rates of recurrence and metastasis. The five-year survival for uLMS patients is between 25 and 76%, with survival rates approaching 10–15% for patients with metastatic disease at the initial diagnosis. Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. […] In this review article, we provide the current state of knowledge by summarizing and discussing the cellular and molecular mechanisms underlying the regulation and emerging role of genetic, epigenetic, and biological pathways in the pathogenesis of uLMS. […] Evidence suggests that uLMS can arise de novo or secondary to malignant degeneration of an LM. uLMS is a malignant mesenchymal neoplasm that arises from the myometrium of the uterus.

• #41 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://pmc.ncbi.nlm.nih.gov/articles/PMC11240800/

  Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. […] Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. […] In this review article, we provide the current state of knowledge by summarizing and discussing the cellular and molecular mechanisms underlying the regulation and emerging role of genetic, epigenetic, and biological pathways in the pathogenesis of uLMS. […] Evidence suggests that uLMS can arise de novo or secondary to malignant degeneration of an LM. uLMS is a malignant mesenchymal neoplasm that arises from the myometrium of the uterus. […] No single driving mutation has been identified for uLMS, but some potential driving mutations have been reported. […] Uterine sarcoma patients in a relatively large cohort sample (n = 145) showed frequently harbored pathogenic alterations in HR-DNA damage repair (DDR)-related genes.

• #42 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://www.mdpi.com/2073-4409/13/13/1106

  The Cancer Genome Atlas project confirmed mutations and deletions in RB1, p53, and PTEN in all LMS, including uLMSs, and an overall low mutational burden in sarcomas compared to other tumors. […] Uterine sarcoma patients in a relatively large cohort sample (n = 145) showed frequently harbored pathogenic alterations in HR-DNA damage repair (DDR)-related genes. […] Studies reveal that LMS harbors defects in components of the HR repair pathways and is sensitive to treatments that induce double-stranded breaks or replication fork arrest. […] The hedgehog (HH) pathway is a conserved evolutionary signaling pathway that controls embryonic development and regulates differentiation, physiological conditions, and normal cell growth. […] The HH pathway was described for the first time in uLMS in 2016 by Garcia et al.

• #43 Leiomyosarcoma | Musculoskeletal Key

  https://musculoskeletalkey.com/leiomyosarcoma-2/

  LMS develop de novo in the wall of the uterus, independent of LM. […] The notion that LMS develop from typical LM via malignant transformation has come to be generally rejected. […] Judging by their epidemiology, their incidence and their morphologic characteristics, it seems highly likely that STUMP can progress into LMS. […] Analyses suggest that p16 might play a role in the pathogenesis of LMS. […] In contrast to LM, LMS often exhibit chromosomal aberrations and genomic instability. […] There are data which suggest that a loss of BRCA1 function may play a role in the pathogenesis of LMS. […] Besides other sarcomas, LMS arise more frequently in patients with inherited p53 mutations (Li-Fraumeni syndrome), which serves to underline the causal-pathogenetic role that p53 mutations play in some LMS.

• #44 Leiomyosarcoma | Musculoskeletal Key

  https://musculoskeletalkey.com/leiomyosarcoma-2/

  LMS develop de novo in the wall of the uterus, independent of LM. […] The notion that LMS develop from typical LM via malignant transformation has come to be generally rejected. […] Judging by their epidemiology, their incidence and their morphologic characteristics, it seems highly likely that STUMP can progress into LMS. […] Analyses suggest that p16 might play a role in the pathogenesis of LMS. […] In contrast to LM, LMS often exhibit chromosomal aberrations and genomic instability. […] There are data which suggest that a loss of BRCA1 function may play a role in the pathogenesis of LMS. […] Besides other sarcomas, LMS arise more frequently in patients with inherited p53 mutations (Li-Fraumeni syndrome), which serves to underline the causal-pathogenetic role that p53 mutations play in some LMS.

• #45 Leiomyosarcoma | Musculoskeletal Key

  https://musculoskeletalkey.com/leiomyosarcoma-2/

  LMS develop de novo in the wall of the uterus, independent of LM. […] The notion that LMS develop from typical LM via malignant transformation has come to be generally rejected. […] Judging by their epidemiology, their incidence and their morphologic characteristics, it seems highly likely that STUMP can progress into LMS. […] Analyses suggest that p16 might play a role in the pathogenesis of LMS. […] In contrast to LM, LMS often exhibit chromosomal aberrations and genomic instability. […] There are data which suggest that a loss of BRCA1 function may play a role in the pathogenesis of LMS. […] Besides other sarcomas, LMS arise more frequently in patients with inherited p53 mutations (Li-Fraumeni syndrome), which serves to underline the causal-pathogenetic role that p53 mutations play in some LMS.

• #46 Location, Location, Location: Approaches to Retroperitoneal Vascular Leiomyosarcoma

  https://www.cancernetwork.com/view/location-location-location-approaches-retroperitoneal-vascular-leiomyosarcoma

  Leiomyosarcoma, one of the most common soft tissue sarcomas, can occur anywhere in the body, but it is frequently found in the abdomen and retroperitoneum. […] Leiomyosarcomas, a subset of soft tissue sarcomas, are malignant smooth muscle neoplasms that account for approximately 5% to 10% of all sarcomas. Natural history is dependent on the anatomic location in which they arise. […] Leiomyosarcomas arising in the middle portion of the IVC (ie, infrahepatic, suprarenal) are the most frequent at about 40%, and symptoms may include a palpable abdominal mass, abdominal or visceral pain, and bilateral lower extremity edema. […] Vascular leiomyosarcomas are derived from smooth muscle cells within the medial layer of blood vessels. […] Leiomyosarcomas originating from the IVC account for approximately 0.5% of soft tissue sarcomas; about 300 of these tumors have been reported in this location in the literature.

• #47 Location, Location, Location: Approaches to Retroperitoneal Vascular Leiomyosarcoma

  https://www.cancernetwork.com/view/location-location-location-approaches-retroperitoneal-vascular-leiomyosarcoma

  Leiomyosarcoma, one of the most common soft tissue sarcomas, can occur anywhere in the body, but it is frequently found in the abdomen and retroperitoneum. […] Leiomyosarcomas, a subset of soft tissue sarcomas, are malignant smooth muscle neoplasms that account for approximately 5% to 10% of all sarcomas. Natural history is dependent on the anatomic location in which they arise. […] Leiomyosarcomas arising in the middle portion of the IVC (ie, infrahepatic, suprarenal) are the most frequent at about 40%, and symptoms may include a palpable abdominal mass, abdominal or visceral pain, and bilateral lower extremity edema. […] Vascular leiomyosarcomas are derived from smooth muscle cells within the medial layer of blood vessels. […] Leiomyosarcomas originating from the IVC account for approximately 0.5% of soft tissue sarcomas; about 300 of these tumors have been reported in this location in the literature.

• #48 On the Origin of Abdominal Venous Leiomyosarcomas: The Role of the Sex-Hormone Drainage Pathways | Tarique | World Journal of Oncology

  https://www.wjon.org/index.php/wjon/article/view/1884/1692

  We hypothesized that abdominal venous leiomyosarcoma (AV-LMS) disproportionately originates in veins of the sex-hormone drainage pathway (SHDP). […] The ovarian vein and mid-IVC represent the drainage pathway of the ovaries and adrenal glands, and as such are exposed to high sex-hormone levels. […] We believe that these findings support our hypothesis that AV-LMS occurrence is concentrated around the SHDP, namely the ovarian and adrenal vein DPs. […] Our findings suggest that LMS arising in SHDP may be independently associated with lower rates of metastatic disease at presentation. […] The high proclivity of adrenal glands/veins for LMS may be because the adrenal glands produce sex-hormones throughout life in both sexes. […] This study found that the ovarian vein is the second most common site of AV-LMS after the IVC and therefore is highly underrecognized as the primary site of disease. […] These findings support the hypothesis that AV-LMS occurs predominantly in the venous DPs of sex-hormone-producing organs.

• #49 On the Origin of Abdominal Venous Leiomyosarcomas: The Role of the Sex-Hormone Drainage Pathways | Tarique | World Journal of Oncology

  https://www.wjon.org/index.php/wjon/article/view/1884/1692

  We hypothesized that abdominal venous leiomyosarcoma (AV-LMS) disproportionately originates in veins of the sex-hormone drainage pathway (SHDP). […] The ovarian vein and mid-IVC represent the drainage pathway of the ovaries and adrenal glands, and as such are exposed to high sex-hormone levels. […] We believe that these findings support our hypothesis that AV-LMS occurrence is concentrated around the SHDP, namely the ovarian and adrenal vein DPs. […] Our findings suggest that LMS arising in SHDP may be independently associated with lower rates of metastatic disease at presentation. […] The high proclivity of adrenal glands/veins for LMS may be because the adrenal glands produce sex-hormones throughout life in both sexes. […] This study found that the ovarian vein is the second most common site of AV-LMS after the IVC and therefore is highly underrecognized as the primary site of disease. […] These findings support the hypothesis that AV-LMS occurs predominantly in the venous DPs of sex-hormone-producing organs.

• #50 On the Origin of Abdominal Venous Leiomyosarcomas: The Role of the Sex-Hormone Drainage Pathways | Tarique | World Journal of Oncology

  https://www.wjon.org/index.php/wjon/article/view/1884/1692

  We hypothesized that abdominal venous leiomyosarcoma (AV-LMS) disproportionately originates in veins of the sex-hormone drainage pathway (SHDP). […] The ovarian vein and mid-IVC represent the drainage pathway of the ovaries and adrenal glands, and as such are exposed to high sex-hormone levels. […] We believe that these findings support our hypothesis that AV-LMS occurrence is concentrated around the SHDP, namely the ovarian and adrenal vein DPs. […] Our findings suggest that LMS arising in SHDP may be independently associated with lower rates of metastatic disease at presentation. […] The high proclivity of adrenal glands/veins for LMS may be because the adrenal glands produce sex-hormones throughout life in both sexes. […] This study found that the ovarian vein is the second most common site of AV-LMS after the IVC and therefore is highly underrecognized as the primary site of disease. […] These findings support the hypothesis that AV-LMS occurs predominantly in the venous DPs of sex-hormone-producing organs.

• #51 On the Origin of Abdominal Venous Leiomyosarcomas: The Role of the Sex-Hormone Drainage Pathways | Tarique | World Journal of Oncology

  https://www.wjon.org/index.php/wjon/article/view/1884/1692

  We hypothesized that abdominal venous leiomyosarcoma (AV-LMS) disproportionately originates in veins of the sex-hormone drainage pathway (SHDP). […] The ovarian vein and mid-IVC represent the drainage pathway of the ovaries and adrenal glands, and as such are exposed to high sex-hormone levels. […] We believe that these findings support our hypothesis that AV-LMS occurrence is concentrated around the SHDP, namely the ovarian and adrenal vein DPs. […] Our findings suggest that LMS arising in SHDP may be independently associated with lower rates of metastatic disease at presentation. […] The high proclivity of adrenal glands/veins for LMS may be because the adrenal glands produce sex-hormones throughout life in both sexes. […] This study found that the ovarian vein is the second most common site of AV-LMS after the IVC and therefore is highly underrecognized as the primary site of disease. […] These findings support the hypothesis that AV-LMS occurs predominantly in the venous DPs of sex-hormone-producing organs.

• #52 Primary adrenal leiomyosarcoma: A case report

  https://www.spandidos-publications.com/10.3892/mco.2020.1987

  Adrenal LMS are non-functional mesenchymal tumors of the adrenal gland, with smooth muscle differentiation, which are thought to derive from the adrenal vein or its branches. […] The pathogenesis of adrenal leiomyosarcoma remains unknown, but there might be a correlation with Epstein-Barr Virus infection in patients with acquired immunodeficiency syndrome (AIDS). […] Their diagnosis is rendered after pathological examination of the specimen, which is observed microscopically as a spindle cell neoplasia with nuclear atypia or pleomorphism, high mitotic activity and necrotic foci and immunohistochemically is found positive for smooth muscle stains, although there have been described cases with pleomorphic presentation of the tumor. […] Adrenal LMS are usually diagnosed after they have reached a large size due to their lack of specific signs and symptoms, and in many cases the tumor is found to have extended to the inferior vena cava (IVC) upon diagnosis, or to have spread to distant organs.

• #53 Primary adrenal leiomyosarcoma: A case report

  https://www.spandidos-publications.com/10.3892/mco.2020.1987

  Adrenal LMS are non-functional mesenchymal tumors of the adrenal gland, with smooth muscle differentiation, which are thought to derive from the adrenal vein or its branches. […] The pathogenesis of adrenal leiomyosarcoma remains unknown, but there might be a correlation with Epstein-Barr Virus infection in patients with acquired immunodeficiency syndrome (AIDS). […] Their diagnosis is rendered after pathological examination of the specimen, which is observed microscopically as a spindle cell neoplasia with nuclear atypia or pleomorphism, high mitotic activity and necrotic foci and immunohistochemically is found positive for smooth muscle stains, although there have been described cases with pleomorphic presentation of the tumor. […] Adrenal LMS are usually diagnosed after they have reached a large size due to their lack of specific signs and symptoms, and in many cases the tumor is found to have extended to the inferior vena cava (IVC) upon diagnosis, or to have spread to distant organs.

• #54 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  Both uLMS and ST-LMS demonstrate fewer SCNAs than more immune-sensitive complex sarcomas, such as UPS. […] The presence of ongoing DNA damage and deficient DNA damage repair mechanisms has been observed to foster inflammatory signaling that results in intratumoral influx of immunosuppressive cells, particularly myeloid-derived suppressor cells and tumor-associated macrophages (TAMs). […] The administration of PARP inhibitors has been observed to produce a more robust infiltration of cytotoxic CD8+ T cells. This has been hypothesized to be a result of cytosolic DNA formation caused by double-strand DNA breaks generated by PARP inhibition, which results in increased secretion of proinflammatory cytokines IL-2, TNFα, and IFNγ, leading to subsequent CD8+ T-cell activation. […] The immune landscape of both ST-LMS and uLMS is characterized by a lower density of intratumoral immune cell infiltration than other sarcoma histologies with complex karyotypes.

• #55 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  The presence of tertiary lymphoid structures (TLS) in the tumor immune microenvironment has gained significant interest because of its association with response to ICB. […] PD-L1 expression is a controversial biomarker of response across tumor types, as its prognostic and predictive value is often imperfect, depends on the type of ICB used, and the method of evaluation of the biomarker. […] The characterization of LMS into distinct molecular subtypes has provided additional insights into the clinical significance of the immune microenvironment.

• #56 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  The presence of tertiary lymphoid structures (TLS) in the tumor immune microenvironment has gained significant interest because of its association with response to ICB. […] PD-L1 expression is a controversial biomarker of response across tumor types, as its prognostic and predictive value is often imperfect, depends on the type of ICB used, and the method of evaluation of the biomarker. […] The characterization of LMS into distinct molecular subtypes has provided additional insights into the clinical significance of the immune microenvironment.

• #57 Separating Treatment of Leiomyosarcomas From STS Umbrella

  https://www.targetedonc.com/view/separating-treatment-of-leiomyosarcomas-from-sts-umbrella

  Leiomyosarcomas are tumors that occur in smooth muscle tissues. They frequently are found in the retroperitoneum, uterus, dermis, and vessels, though they can also occur in the bone. They are pleomorphic myogenic sarcomas that are commonly aggressive and associated with a shorter relapse-free survival. […] Prognostic factors for leiomyosarcomas are strongly tied to the location of the tumor and its size. Retroperitoneal and vascular tumors have a poorer prognosis, whereas cutaneous leiomyosarcomas have a better prognosis than some of the other subtypes. Patients with hereditary retinoblastomas caused by a germline RB1 mutation have an increased risk of developing STS, especially leiomyosarcomas. […] Leiomyosarcoma is 1 of the STS subtypes that has shown a high proportion of PD-L1 expression. In a study of PD-1 and PD-L1 expression in STS, 58% of samples showed PD-L1 expression. Among patients with leiomyosarcoma, 45% had PD-1 positive expression and 70% had PD-L1 expression. Interestingly, with STS, expression was associated with a poor prognosis by multivariate analysis. Among patients with leiomyosarcoma, PD-1/PD-L1 positivity also tended to be found in those with a higher tumor stage, also accounting for a poor prognosis. The true impact of checkpoint inhibitors on patients with leiomyosarcoma is still unknown.

• #58 Leiomyosarcoma | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/24180

  Leiomyosarcomas are primarily associated with RB1 and PTEN tumor suppressor gene mutations. RB1 gene mutations are observed in 90% of patients. The cytogenetic and molecular changes in leiomyosarcoma are inconsistent, contributing to its highly heterogeneous nature. More recent data from The Cancer Genome Atlas revealed that leiomyosarcoma, like other STSs, is associated with a lower tumor mutational burden compared to other types of cancers. […] Although there are no definite causative factors for leiomyosarcoma, certain risk factors have been associated with developing STSs, including leiomyosarcoma. The significant risk factor for STS is a history of radiation exposure or radiotherapy, particularly at a young age. STSs may also be part of genetic syndromes, such as retinoblastoma (due to RB1 gene deletion) and Li-Fraumeni syndrome (caused by a mutation in the TP53 gene).

• #59 Leiomyosarcoma – wikidoc

  https://www.wikidoc.org/index.php/Leiomyosarcoma

  The pathogenesis of leimyosarcoma is characterized by malignant smooth muscle neoplasm that can appear in any site in the body but most commonly found in the uterus, small intestine and retro peritoneum. […] Exact cause of leiomyosarcoma is not clearly evident because of the rarety of disease nature. It may arise denovo or by genetic instability. […] Clinical data has suggested that the development of leiomyosarcoma is related to radiation exposure. Other risk factors include use of tamoxifen, immunodeficiency, viral infection.

• #60 Leiomyosarcoma | Musculoskeletal Key

  https://musculoskeletalkey.com/leiomyosarcoma-2/

  The frequency to which the medical histories of patients with LMS reveal previous tamoxifen ingestion has been on the increase. […] LMS growth is generally regarded as being estrogen independent, a view that is supported by the fact that LMS can progress under treatment with GnRH analogues. […] In contrast to other genital sarcomas, previous pelvic RT apparently does not play a role in the pathogenesis of LMS.

• #61 Leiomyosarcoma | Musculoskeletal Key

  https://musculoskeletalkey.com/leiomyosarcoma-2/

  The frequency to which the medical histories of patients with LMS reveal previous tamoxifen ingestion has been on the increase. […] LMS growth is generally regarded as being estrogen independent, a view that is supported by the fact that LMS can progress under treatment with GnRH analogues. […] In contrast to other genital sarcomas, previous pelvic RT apparently does not play a role in the pathogenesis of LMS.

• #62 Leiomyosarcoma | Musculoskeletal Key

  https://musculoskeletalkey.com/leiomyosarcoma-2/

  The frequency to which the medical histories of patients with LMS reveal previous tamoxifen ingestion has been on the increase. […] LMS growth is generally regarded as being estrogen independent, a view that is supported by the fact that LMS can progress under treatment with GnRH analogues. […] In contrast to other genital sarcomas, previous pelvic RT apparently does not play a role in the pathogenesis of LMS.

• #63 Leiomyosarcoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551667/

  Leiomyosarcomas are primarily associated with RB1 and PTEN tumor suppressor gene mutations. RB1 gene mutations are observed in 90% of patients. The cytogenetic and molecular changes in leiomyosarcoma are inconsistent, contributing to its highly heterogeneous nature. More recent data from The Cancer Genome Atlas revealed that leiomyosarcoma, like other STSs, is associated with a lower tumor mutational burden compared to other types of cancers. […] Leiomyosarcoma is a tumor with complex and unbalanced karyotypes characterized by severe genomic instability, which results in multiple genetic aberrations. As a result, leiomyosarcoma is considered moderately sensitive to chemotherapy. […] Leiomyosarcoma staging is according to the organ of origin. Uterine leiomyosarcoma staging follows the Federation of Gynecology and Obstetrics (FIGO) staging system. According to the American Joint Committee of Cancer (AJCC) staging, an extrauterine leiomyosarcoma gets staged. However, the 8th edition of AJCC has resolved a long-standing variability in STS staging. In the latest edition, AJCC has provided a separate staging system for STS of the retroperitoneum, head or neck region, and extremities or trunk region.

• #64 Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12 | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005850

  Immunohistochemical analysis including 50 ULMSs confirmed altered expression in the majority of tumors, highlighting the role of TP53 in ULMS development. […] Loss of ATRX expression has been reported in leiomyosarcomas of various sites and a recent meeting abstract on ULMSs reported genomic alterations of this gene in 32% (8/25) of the studied tumors, supporting our findings. […] Importantly, ALT was recently suggested to render cancer cells hypersensitive to ATR inhibitors. […] While MED12 mutations are the most common alterations in benign conventional leiomyomas, TP53 or ATRX mutations have not been observed in these tumors. […] Specifically, identification of inactivating ATRX mutations and their association with the ALT phenotype in the substantial proportion of tumors may be translatable into clinical practice should the suggested effect of ATR inhibitors prove effective.

• #65 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  We have shown TP53 and RB1 inactivation in 90% of LMS, and TP53 and RB1 inactivating germline mutations are initiating events in LMS. […] Project 1 seeks to develop therapies that maximize intrinsic LMS genotoxic stress by targeting the key DNA damage response enzyme, DNA-PK. […] A genome-wide shRNA long-term screen identified genes with essential roles in early-passage LMS lines. […] These observations are the rationale for the overarching Project 1 hypothesis, which is that the intrinsic CIN in advanced LMS is a vulnerability that can be exploited, using doxorubicin coupled with targeted inhibitors, particularly DNA-PK inhibitors. […] Project 2 focuses on studying the genetic epidemiology of LMS defining the risk for cancer in families with cancer predisposition syndromes such as Li-Fraumeni Syndrome, as well as the general population by evaluating the largest ever cohort of LMS patients.

• #66 Leiomyosarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/leiomyosarcoma/

  Similarly, the function of RB1 is disrupted in nearly all cases of soft tissue LMS by diverse mechanisms that either target RB1 itself or result in altered expression of CDKN2A, CCND1, CCND2, or CDK4. […] Potentially deleterious ATRX alterations have been observed in 16–49% of cases and probably contribute to the high prevalence of alternative lengthening of telomeres in LMS. […] ALK rearrangements have been identified in a small subset of LMSs (9 of 377 cases; 2.4%) arising in males and females (soft tissue and uterine), imparting potential for clinically actionable opportunities. […] Gene expression studies suggest that there are multiple subgroups of LMS, including a muscle-enriched subtype and less-differentiated groupings, with indications of differing frequencies of specific genomic changes and varying prognoses.

• #67 Leiomyosarcoma – SFA

  https://curesarcoma.org/sarcoma-subtypes/leiomyosarcoma/

  Similarly, the function of RB1 is disrupted in nearly all cases of soft tissue LMS by diverse mechanisms that either target RB1 itself or result in altered expression of CDKN2A, CCND1, CCND2, or CDK4. […] Potentially deleterious ATRX alterations have been observed in 16–49% of cases and probably contribute to the high prevalence of alternative lengthening of telomeres in LMS. […] ALK rearrangements have been identified in a small subset of LMSs (9 of 377 cases; 2.4%) arising in males and females (soft tissue and uterine), imparting potential for clinically actionable opportunities. […] Gene expression studies suggest that there are multiple subgroups of LMS, including a muscle-enriched subtype and less-differentiated groupings, with indications of differing frequencies of specific genomic changes and varying prognoses.

• #68 Targeting the Molecular and Immunologic Features of Leiomyosarcoma

  https://www.mdpi.com/2072-6694/15/7/2099

  Both uLMS and ST-LMS demonstrate fewer SCNAs than more immune-sensitive complex sarcomas, such as UPS. […] The presence of ongoing DNA damage and deficient DNA damage repair mechanisms has been observed to foster inflammatory signaling that results in intratumoral influx of immunosuppressive cells, particularly myeloid-derived suppressor cells and tumor-associated macrophages (TAMs). […] The administration of PARP inhibitors has been observed to produce a more robust infiltration of cytotoxic CD8+ T cells. This has been hypothesized to be a result of cytosolic DNA formation caused by double-strand DNA breaks generated by PARP inhibition, which results in increased secretion of proinflammatory cytokines IL-2, TNFα, and IFNγ, leading to subsequent CD8+ T-cell activation. […] The immune landscape of both ST-LMS and uLMS is characterized by a lower density of intratumoral immune cell infiltration than other sarcoma histologies with complex karyotypes.

• #69 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  We have shown TP53 and RB1 inactivation in 90% of LMS, and TP53 and RB1 inactivating germline mutations are initiating events in LMS. […] Project 1 seeks to develop therapies that maximize intrinsic LMS genotoxic stress by targeting the key DNA damage response enzyme, DNA-PK. […] A genome-wide shRNA long-term screen identified genes with essential roles in early-passage LMS lines. […] These observations are the rationale for the overarching Project 1 hypothesis, which is that the intrinsic CIN in advanced LMS is a vulnerability that can be exploited, using doxorubicin coupled with targeted inhibitors, particularly DNA-PK inhibitors. […] Project 2 focuses on studying the genetic epidemiology of LMS defining the risk for cancer in families with cancer predisposition syndromes such as Li-Fraumeni Syndrome, as well as the general population by evaluating the largest ever cohort of LMS patients.

• #70 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://ouci.dntb.gov.ua/en/works/lDpBXoYl/

  Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. […] Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. […] The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis.

• #71 Separating Treatment of Leiomyosarcomas From STS Umbrella

  https://www.targetedonc.com/view/separating-treatment-of-leiomyosarcomas-from-sts-umbrella

  Leiomyosarcomas are tumors that occur in smooth muscle tissues. They frequently are found in the retroperitoneum, uterus, dermis, and vessels, though they can also occur in the bone. They are pleomorphic myogenic sarcomas that are commonly aggressive and associated with a shorter relapse-free survival. […] Prognostic factors for leiomyosarcomas are strongly tied to the location of the tumor and its size. Retroperitoneal and vascular tumors have a poorer prognosis, whereas cutaneous leiomyosarcomas have a better prognosis than some of the other subtypes. Patients with hereditary retinoblastomas caused by a germline RB1 mutation have an increased risk of developing STS, especially leiomyosarcomas. […] Leiomyosarcoma is 1 of the STS subtypes that has shown a high proportion of PD-L1 expression. In a study of PD-1 and PD-L1 expression in STS, 58% of samples showed PD-L1 expression. Among patients with leiomyosarcoma, 45% had PD-1 positive expression and 70% had PD-L1 expression. Interestingly, with STS, expression was associated with a poor prognosis by multivariate analysis. Among patients with leiomyosarcoma, PD-1/PD-L1 positivity also tended to be found in those with a higher tumor stage, also accounting for a poor prognosis. The true impact of checkpoint inhibitors on patients with leiomyosarcoma is still unknown.

• #72 Exploiting the therapeutic efficacy of eribulin in leiomyosarcoma through a better knowledge of its complex mechanism of action – SFA

  https://curesarcoma.org/funded-research/exploiting-the-therapeutic-efficacy-of-eribulin-in-leiomyosarcoma-through-a-better-knowledge-of-its-complex-mechanism-of-action/

  Leiomyosarcoma (LMS) is one of the most common soft tissue sarcomas, representing up to 20% of all of them. […] Systemic therapies for advanced or metastatic LMS are still a major challenge, with a median survival time of just 1 year. […] However, objective responses were observed in several LMS patients, making the pharmacological effect of this compound worth further investigation. Indeed, eribulin has a complex mechanism of action that includes non-mitotic effects such as differentiation, with increased expression of smooth muscle markers in a LMS cell line. […] Demonstrating the relevance of the non-mitotic effect of eribulin in LMS could change the paradigm of its clinical use, not only as a pure cytotoxic agent but also as an adjuvant able to synergize with other drugs. […] Since molecular heterogeneity is a major determinant of tumor response to specific anticancer agents, we will perform RNAseq studies to identify the pathways involved in sensitivity to or resistance against eribulin, focusing on those related to smooth muscle differentiation. […] A better knowledge of the mechanism of action of eribulin will help us to design new strategies to exploit the pharmacological properties of this compound in LMS.

• #73 Leiomyosarcoma – Libre Pathology

  https://librepathology.org/wiki/Leiomyosarcoma

  Leiomyosarcoma is a malignant tumour of smooth muscle. It is seen in various places including the uterus and skin. […] Poor prognosis – usually. In locally advanced/metastatic disease (arising from the uterus) the median survival is 12-14 months. […] Do not (generally) arise from leiomyomas. […] May be a part of hereditary leiomyomatosis and renal cell cancer. […] Features of malignancy (usually need 2 of 3): Nuclear atypia. Tumour cell necrosis. Mitoses – key feature – definitions suffer from HPFitis. […] Mitotic rate seems to be a relatively weak predictor; modest rate may be malignant and a high rate benign. […] Leiomyosarcoma de facto trumps other sarcomas.

• #74 Exploiting the therapeutic efficacy of eribulin in leiomyosarcoma through a better knowledge of its complex mechanism of action – SFA

  https://curesarcoma.org/funded-research/exploiting-the-therapeutic-efficacy-of-eribulin-in-leiomyosarcoma-through-a-better-knowledge-of-its-complex-mechanism-of-action/

  Leiomyosarcoma (LMS) is one of the most common soft tissue sarcomas, representing up to 20% of all of them. […] Systemic therapies for advanced or metastatic LMS are still a major challenge, with a median survival time of just 1 year. […] However, objective responses were observed in several LMS patients, making the pharmacological effect of this compound worth further investigation. Indeed, eribulin has a complex mechanism of action that includes non-mitotic effects such as differentiation, with increased expression of smooth muscle markers in a LMS cell line. […] Demonstrating the relevance of the non-mitotic effect of eribulin in LMS could change the paradigm of its clinical use, not only as a pure cytotoxic agent but also as an adjuvant able to synergize with other drugs. […] Since molecular heterogeneity is a major determinant of tumor response to specific anticancer agents, we will perform RNAseq studies to identify the pathways involved in sensitivity to or resistance against eribulin, focusing on those related to smooth muscle differentiation. […] A better knowledge of the mechanism of action of eribulin will help us to design new strategies to exploit the pharmacological properties of this compound in LMS.

• #75 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  The project will identify germline pathogenic variants (PVs) in TP53, and other DNA damage repair (DDR) genes in patients with LMS. […] Project 2 also seeks to identify previously unrecognized genes and pathways conferring risk of LMS development. […] Our hypothesis is that comprehensive assessment of germline DNA of cancer predisposition genes in patients with LMS and LFS will identify families at increased risk of LMS who may benefit from enhanced cancer screening. […] The results from Project 2 will reveal important insights into the genetic basis of LMS, directly impact future risk management and treatment of patients at risk for LMS, and establish a global infrastructure to enable future research into the genetic basis for this disease. […] Hypothesis: ctDNA may be used as a biomarker of LMS patient prognosis and tumor response to chemotherapy. […] We will collect and analyze serial liquid biopsy and tumor samples to validate ctDNA plasma levels as a biomarker in patients with metastatic LMS and to perform deep genomic profiling of this tumor DNA to describe recurrent patterns of tumor evolution and treatment resistance in this disease.

• #76 Genetics and Genomics of Leiomyosarcoma (LMS): Improved understanding of cancer biology and new approaches to diagnosis and treatment

  https://trp.cancer.gov/spores/abstracts/umich_sarcoma.htm

  The project will identify germline pathogenic variants (PVs) in TP53, and other DNA damage repair (DDR) genes in patients with LMS. […] Project 2 also seeks to identify previously unrecognized genes and pathways conferring risk of LMS development. […] Our hypothesis is that comprehensive assessment of germline DNA of cancer predisposition genes in patients with LMS and LFS will identify families at increased risk of LMS who may benefit from enhanced cancer screening. […] The results from Project 2 will reveal important insights into the genetic basis of LMS, directly impact future risk management and treatment of patients at risk for LMS, and establish a global infrastructure to enable future research into the genetic basis for this disease. […] Hypothesis: ctDNA may be used as a biomarker of LMS patient prognosis and tumor response to chemotherapy. […] We will collect and analyze serial liquid biopsy and tumor samples to validate ctDNA plasma levels as a biomarker in patients with metastatic LMS and to perform deep genomic profiling of this tumor DNA to describe recurrent patterns of tumor evolution and treatment resistance in this disease.

• #77 MDPI Cells: Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy (Bishop Lab) – Greehey Children’s Cancer

  https://gccri.uthscsa.edu/2024/07/15/mdpi-cells-comprehensive-review-of-uterine-leiomyosarcoma-pathogenesis-diagnosis-prognosis-and-targeted-therapy-bishop-lab/

  Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. […] Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. […] In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. […] We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. […] Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor.

• #78 Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy

  https://knowledge.uchicago.edu/record/12745?ln=en

  Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. […] Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. […] In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS, from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. […] We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. […] Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor.

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