-
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 -
The New England Journal of Medicine Aug 2018
Review
Topics: Abdominal Pain; Adenocarcinoma; Cecum; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Combined Modality Therapy; DNA Mismatch Repair; Genetic Counseling; Humans; Male; Middle Aged; Practice Guidelines as Topic
PubMed: 30134129
DOI: 10.1056/NEJMcp1714533 -
Gastrointestinal Endoscopy Clinics of... Jan 2022Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes,... (Review)
Review
Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by pathogenic germline variants (PGV) in any of the 4 DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, or deletions in EPCAM. LS leads to an increased risk of intestinal and extraintestinal cancers, of which colorectal and endometrial cancers are the most common. Individuals at risk for LS can be identified by using clinical criteria, prediction models, and universal tumor testing. Understanding each of these tools, including limitations and mimics of LS, is essential to the early identification of at-risk individuals.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; MutL Protein Homolog 1
PubMed: 34798986
DOI: 10.1016/j.giec.2021.09.002 -
Nature Reviews. Cancer Mar 2015Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers,... (Review)
Review
Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; History, 19th Century; History, 20th Century; History, 21st Century
PubMed: 25673086
DOI: 10.1038/nrc3878 -
Best Practice & Research. Clinical... 2022Lynch syndrome is the most common inherited cause of colorectal (lifetime risk up to 70%) and endometrial cancer. The diagnosis of Lynch syndrome facilitates preventive... (Review)
Review
Lynch syndrome is the most common inherited cause of colorectal (lifetime risk up to 70%) and endometrial cancer. The diagnosis of Lynch syndrome facilitates preventive measures aimed at reducing the incidence and mortality of cancer. Colonoscopic surveillance for colorectal cancer, aspirin, and prophylactic hysterectomy and bilateral salpo-oopherectomy for endometrial and/or ovarian cancer have demonstrated to effectively reduce cancer mortality in this population. However, the lifetime risk of each cancer in people with Lynch syndrome is gene-specific and may be modified by environmental factors. Furthermore, the benefits of surveillance strategies need to be balanced against the risk of over-diagnosis and be supported by evidence of improved outcomes from cancer diagnosis in surveillance. Therefore, people with Lynch syndrome may benefit from a personalized management approach.
Topics: Colonoscopy; Colorectal Neoplasms, Hereditary Nonpolyposis; Endometrial Neoplasms; Female; Humans; Incidence; Ovarian Neoplasms
PubMed: 35988964
DOI: 10.1016/j.bpg.2022.101790 -
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 -
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 -
Clinical Obstetrics and Gynecology Jun 2011Almost 100 years ago Lynch syndrome was discovered by Dr Aldred Warthin. Initially, the syndrome was named Hereditary Nonpolyposis Colorectal Cancer as colorectal cancer... (Review)
Review
Almost 100 years ago Lynch syndrome was discovered by Dr Aldred Warthin. Initially, the syndrome was named Hereditary Nonpolyposis Colorectal Cancer as colorectal cancer seemed most prevalent. Over time uterine cancer and several other malignancies were recognized as part of the spectrum. This autosomal-dominant inherited cancer syndrome is characterized by a defect in mismatch repair genes and puts patients at a significantly increased risk for colorectal and uterine cancer. Recognition and diagnosis of Lynch syndrome is extremely important so that appropriate screening programs and/or risk-reducing surgery can be initiated to prevent development or promote early detection of cancers.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Early Detection of Cancer; Endometrial Neoplasms; Female; Humans; Ovarian Neoplasms
PubMed: 21508689
DOI: 10.1097/GRF.0b013e3182185a41 -
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