-
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 -
International Journal of Cancer Jan 2022Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial... (Review)
Review
Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS-EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS-EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry (MMR-IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS-EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) EC.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair Enzymes; Endometrial Neoplasms; Female; Germ-Line Mutation; Humans; Microsatellite Instability
PubMed: 34398969
DOI: 10.1002/ijc.33763 -
American Journal of Human Genetics Jan 2021The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier...
The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed "variants of uncertain significance" (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians' interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genetic Predisposition to Disease; HEK293 Cells; Humans; MutS Homolog 2 Protein; Mutation, Missense
PubMed: 33357406
DOI: 10.1016/j.ajhg.2020.12.003 -
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 -
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 -
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 -
International Journal of Molecular... Jan 2023Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and... (Review)
Review
Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome ( gene), -associated polyposis ( gene), Peutz-Jeghers syndrome ( gene), Cowden syndrome ( gene), and juvenile polyposis syndrome ( and genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as , , , , , , and . In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
Topics: Humans; Genetic Predisposition to Disease; Adenomatous Polyposis Coli; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Testing; Colorectal Neoplasms
PubMed: 36768460
DOI: 10.3390/ijms24032137 -
BJS Open May 2023Inheritance patterns show familial clustering of gastrointestinal cancers, and multiple germline conditions have now been identified that predispose to colorectal,... (Review)
Review
BACKGROUND
Inheritance patterns show familial clustering of gastrointestinal cancers, and multiple germline conditions have now been identified that predispose to colorectal, gastric, and pancreatic cancers.
METHODS
A narrative review based on recent relevant literature was conducted.
RESULTS
Lynch syndrome, formerly known as hereditary non-polyposis colorectal cancer, increases the risk of several abdominal cancers, with the highest population prevalence. Familial adenomatous polyposis and some of the more infrequent polyposis syndromes have distinct characteristics affecting various organ-specific cancer risks. Hereditary gastric and pancreatic cancer syndromes include those also causing colorectal cancer, while additional genetic disorders predisposing only to upper gastrointestinal malignancies have been recognized more recently. Diagnosing and managing hereditary cancer syndromes requires multidisciplinary expertise and may be best managed in tertiary centres, with a need to consider patient preference and ensure shared decision-making.
CONCLUSION
Several germline conditions predispose to colorectal, gastric, and pancreatic cancer, which inform identification, surveillance regimens, prevention, cascade screening, counselling, and surgical management. The authors describe developments in the hereditary origin of colorectal, gastric, and pancreatic cancer with current recommendations in surveillance and surgical management.
Topics: Humans; Adenomatous Polyposis Coli; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms; Gastrointestinal Neoplasms; Pancreatic Neoplasms
PubMed: 37165697
DOI: 10.1093/bjsopen/zrad023 -
Genetics in Medicine : Official Journal... Jan 2020Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age... (Observational Study)
Observational Study
PURPOSE
Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.
METHODS
We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.
RESULTS
There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.
CONCLUSION
Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
Topics: Adult; Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA-Binding Proteins; Databases, Genetic; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Mutation; Penetrance; Prospective Studies; Risk Assessment; Sex Characteristics; Survival Analysis
PubMed: 31337882
DOI: 10.1038/s41436-019-0596-9 -
Molecular Aspects of Medicine Oct 2019The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new... (Review)
Review
The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.
Topics: Adenomatous Polyposis Coli; Alleles; Biomarkers; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Predisposition to Disease; Genetic Variation; Germ-Line Mutation; Humans
PubMed: 30862463
DOI: 10.1016/j.mam.2019.03.001