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Bulletin Du Cancer 2019Lynch syndrome is a genetic condition defined by a germline mutation of an MMR (MisMatch Repair) gene leading to a defective DNA MMR system. Therefore, it is... (Review)
Review
Lynch syndrome is a genetic condition defined by a germline mutation of an MMR (MisMatch Repair) gene leading to a defective DNA MMR system. Therefore, it is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer (CRC) and endometrial cancer (EC). Lynch syndrome-related CRC accounts for 3% of all CRC. Lynch syndrome also accounts for 2% of all EC. In case of Lynch syndrome, there is usually a familial history of cancer defined by the Amsterdam and Bethesda criteria. Diagnosis is made by tumor testing with (i) MMR immunohistochemistry and (ii) PCR for MSI (microsatellite instability), a genetic phenotype that characterizes these tumors. MSI can also be detected in sporadic tumors, through epigenetic events inactivating the MMR system. Progress in diagnosis and molecular biology has allowed for better identification of Lynch patients but also other rare genetic syndromes. MSI tumors can now benefit from new treatments such as immunotherapy which underlines the importance of their diagnosis. Finally, patients with Lynch syndrome as well as their relatives, undergo specific surveillance in order to prevent development of other cancers. This review will summarize the different aspects of Lynch syndrome and also focus on recent progress on the topic.
Topics: Algorithms; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Endometrial Neoplasms; Female; Genetic Predisposition to Disease; Humans; Male; Molecular Diagnostic Techniques; Risk
PubMed: 30527816
DOI: 10.1016/j.bulcan.2018.10.009 -
Familial Cancer Apr 2019Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well... (Review)
Review
Lynch syndrome is one of the most common hereditary cancer predisposition syndromes and is associated with increased risks of colorectal and endometrial cancer, as well as multiple other cancer types. While the mechanism of mismatch repair deficiency and microsatellite instability and its role in Lynch-associated carcinogenesis has been known for some time, there have been significant advances recently in diagnostic testing and the understanding of the molecular pathogenesis of Lynch tumors. There is also an increased awareness that the clinical phenotype and cancer risk varies by specific mismatch repair mutation, which in turn has implications on surveillance strategies for patients. Even the treatment of Lynch-associated cancers has changed with the addition of immunotherapy for advanced disease. This progress report aims to review some of the many advances in epidemiology, molecular pathogenesis, diagnosis, clinical phenotype, cancer surveillance, treatment, and chemo- and immune-prevention strategies in the Lynch syndrome field over the past 5 years.
Topics: Antineoplastic Agents, Immunological; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genetic Predisposition to Disease; Genetic Testing; Humans; Microsatellite Instability; Mutation; Phenotype; Prevalence; Randomized Controlled Trials as Topic; Treatment Outcome; Watchful Waiting
PubMed: 30627969
DOI: 10.1007/s10689-018-00117-1 -
Gastroenterology Apr 2023Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in humans and accounts for some 3% of unselected patients with colorectal or endometrial...
Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in humans and accounts for some 3% of unselected patients with colorectal or endometrial cancer and 10%-15% of those with DNA mismatch repair-deficient tumors. Previous studies have established the genetic basis of LS predisposition, but there have been significant advances recently in the understanding of the molecular pathogenesis of LS tumors, which has important implications in clinical management. At the same time, immunotherapy has revolutionized the treatment of advanced cancers with DNA mismatch repair defects. We aim to review the recent progress in the LS field and discuss how the accumulating epidemiologic, clinical, and molecular information has contributed to a more accurate and complete picture of LS, resulting in genotype- and immunologic subtype-specific strategies for surveillance, cancer prevention, and treatment.
Topics: Female; Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Colorectal Neoplasms; Endometrial Neoplasms; Genotype; DNA Mismatch Repair; Microsatellite Instability
PubMed: 36706841
DOI: 10.1053/j.gastro.2022.08.058 -
Frontiers in Immunology 2021Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and... (Review)
Review
Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome - a hereditary cause of dMMR - confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability - high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.
Topics: Biomarkers, Tumor; Cancer Vaccines; Clinical Trials as Topic; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Disease Management; Drug Repositioning; Drug Resistance; Frameshift Mutation; Humans; INDEL Mutation; Immune Checkpoint Inhibitors; Microsatellite Instability; Models, Genetic; Models, Immunological; Translational Science, Biomedical
PubMed: 34630437
DOI: 10.3389/fimmu.2021.757804 -
American Society of Clinical Oncology... May 2018Identification of individuals with inherited predispositions to cancer, including Lynch syndrome, can help prevent cancer and cancer-related death by allowing for the... (Review)
Review
Identification of individuals with inherited predispositions to cancer, including Lynch syndrome, can help prevent cancer and cancer-related death by allowing for the uptake of specific cancer prevention and screening as well as the use of therapies directed toward the underlying neoplastic process for individuals with advanced cancer. In the 25 years since the discovery of microsatellite instability (MSI) and the first recognition of germline mismatch repair (MMR) gene variants as the etiologic basis of Lynch syndrome, there has been tremendous progress in the understanding of the spectrum of cancer risk associated with Lynch syndrome as well as in cancer prevention and risk-reduction strategies. The past few years, in particular, have brought transformative changes in the treatment of Lynch syndrome-associated cancers with immune checkpoint inhibitors. In parallel, advances in next-generation sequencing (NGS) technologies now allow rapid and scalable somatic and germline sequencing that promises to help identify Lynch syndrome in individuals who otherwise lack classic phenotypes. Last, real progress is being made to understand more sophisticated methods of precision cancer prevention, including chemotherapeutic prevention agents (e.g., aspirin) and strategies that leverage the immune system to facilitate primary cancer prevention in otherwise-healthy Lynch syndrome carriers.
Topics: Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Management; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Humans; Immunotherapy; Molecular Targeted Therapy
PubMed: 30231390
DOI: 10.1200/EDBK_208341 -
CA: a Cancer Journal For Clinicians May 2018The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering... (Review)
Review
The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape-altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm-shifting approaches to treatment of Lynch-syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217-231. © 2018 American Cancer Society.
Topics: Adenoma; Cell Transformation, Neoplastic; Chemoprevention; Chemotherapy, Adjuvant; Colectomy; Colonoscopy; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mutational Analysis; Genetic Testing; Germ-Line Mutation; Humans; Sequence Analysis, DNA
PubMed: 29485237
DOI: 10.3322/caac.21448 -
The British Journal of Surgery May 2021Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently...
BACKGROUND
Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged.
METHODS
The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds.
RESULTS
Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided.
CONCLUSION
The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chemoprevention; Colonoscopy; Colorectal Neoplasms, Hereditary Nonpolyposis; Delphi Technique; Digestive System Surgical Procedures; Early Detection of Cancer; Female; Genetic Carrier Screening; Genetic Testing; Genital Neoplasms, Female; Humans; Life Style; Prophylactic Surgical Procedures
PubMed: 34043773
DOI: 10.1002/bjs.11902 -
Gastroenterology Sep 2015Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However,...
BACKGROUND & AIMS
Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome.
METHODS
We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing.
RESULTS
Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%).
CONCLUSIONS
In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.
Topics: Adult; Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mutational Analysis; Female; Gene Expression Profiling; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Heredity; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Pedigree; Phenotype; Predictive Value of Tests; Risk Assessment; Risk Factors
PubMed: 25980754
DOI: 10.1053/j.gastro.2015.05.006 -
Journal of Clinical Oncology : Official... Feb 2019Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial...
PURPOSE
Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.
METHODS
MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.
RESULTS
Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.
CONCLUSION
MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.
Topics: Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Female; Genetic Predisposition to Disease; Humans; Male; Microsatellite Instability; Middle Aged; Mutation; New York City; Phenotype; Prevalence; Prospective Studies; Transcriptome
PubMed: 30376427
DOI: 10.1200/JCO.18.00283 -
BMC Cancer Sep 2017Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical,...
BACKGROUND
Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America.
METHODS
Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.
RESULTS
We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.
CONCLUSION
The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.
Topics: Adult; Colorectal Neoplasms, Hereditary Nonpolyposis; Computational Biology; DNA Mismatch Repair; Female; Founder Effect; Genetic Counseling; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Germ-Line Mutation; Humans; Latin America; Male; Middle Aged; Population Surveillance; RNA Splicing; Registries; Risk Factors
PubMed: 28874130
DOI: 10.1186/s12885-017-3599-4