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Bulletin Du Cancer Feb 2019Microsatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with... (Review)
Review
Microsatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with Lynch syndrome. Lynch syndrome represents one of the most frequent conditions of cancer predisposition in human, thus requiring specific care and genetic counseling. Moreover, research has recently focused increasingly on MMR deficiency due to its positive predictive value for the efficacy of immune checkpoints inhibitors (ICKi) in metastatic tumors, regardless of their primary origin. MSI has also been demonstrated to constitute an independent prognostic factor in several tumor types, being also associated with alternative response to chemotherapy. These observations have led many professional medical organizations to recommend universal screening of all newly diagnosed colorectal cancers for dMMR/MSI status and increasing evidence support the evaluation of MSI in all human tumors regardless of the cancer tissue of origin. Currently, two standard reference methods, namely immunohistochemistry and polymerase chain reaction, are recommended for the detection of dMMR/MSI status. These methods are equally valid as the initial screening test for dMMR/MSI in colorectal cancer. To date, there is no recommendation for the detection of dMMR/MSI in other primary tumors. In this review, we will present a comprehensive overview of the methods used for evaluation of tumor dMMR/MSI status in colorectal cancer, as well as in other tumor sites. We will see that the evaluation of this status remains challenging in some clinical settings, with the need to improve the above methods in these specific contexts.
Topics: Algorithms; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Repair Enzymes; Humans; Immunohistochemistry; Mass Screening; Microsatellite Instability; Polymerase Chain Reaction
PubMed: 30713006
DOI: 10.1016/j.bulcan.2018.12.008 -
Journal of the National Cancer Institute Feb 2004Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic...
Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.
Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair; DNA-Binding Proteins; Genetic Predisposition to Disease; Humans; Microsatellite Repeats; MutL Protein Homolog 1; MutS Homolog 2 Protein; Mutation; Neoplasm Proteins; Nuclear Proteins; Polymerase Chain Reaction; Practice Guidelines as Topic; Proto-Oncogene Proteins; Sensitivity and Specificity; United States
PubMed: 14970275
DOI: 10.1093/jnci/djh034 -
Gut Jul 2018Most patients with gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for... (Observational Study)
Observational Study
BACKGROUND
Most patients with gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.
OBJECTIVE AND DESIGN
This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in carriers up to 75 years of age.
RESULTS
3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_, path_ and path_ carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. carriers had lower risk for cancer.
CONCLUSION
Carriers of different variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and variant. We have updated our open-access website www.lscarisk.org to facilitate this.
Topics: Age Factors; Aged; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Databases, Factual; Female; Humans; Incidence; Male; Pancreatic Neoplasms; Prospective Studies; Urogenital Neoplasms
PubMed: 28754778
DOI: 10.1136/gutjnl-2017-314057 -
Alimentary Pharmacology & Therapeutics Apr 2022Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to... (Review)
Review
BACKGROUND
Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers.
AIM
To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS.
METHODS
A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted.
RESULTS
LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene.
CONCLUSIONS
As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genetic Testing; Humans; Microsatellite Instability
PubMed: 35315099
DOI: 10.1111/apt.16826 -
The Journal of Pathology Oct 2018Recent work has provided evidence for genetic and molecular heterogeneity in colorectal cancers (CRCs) arising in patients with Lynch syndrome (LS), dividing these into... (Review)
Review
Recent work has provided evidence for genetic and molecular heterogeneity in colorectal cancers (CRCs) arising in patients with Lynch syndrome (LS), dividing these into two groups: G1 and G2. In terms of mutation and gene expression profile, G1 CRCs bear resemblance to sporadic CRCs with microsatellite instability (MSI), whereas G2 CRCs are more similar to microsatellite-stable CRCs. Here we review the current state of knowledge on pathways of precursor progression to CRC in LS and how these might tie in with the new findings. Immunotherapies are an active field of research for MSI cancers and their potential use for cancer therapy for both sporadic and LS MSI cancers is discussed. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Animals; Biomarkers, Tumor; Colorectal Neoplasms, Hereditary Nonpolyposis; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Microsatellite Instability; Mutation; Phenotype; Prognosis; Risk Assessment; Risk Factors; Transcriptome; Tumor Escape
PubMed: 30027543
DOI: 10.1002/path.5139 -
Journal of Visceral Surgery Dec 2019Nearly 5% of colorectal cancers are related to constitutional genetic abnormalities. In Lynch Syndrome (LS), the abnormality is a mutation of the deoxyribonucleic acid... (Review)
Review
Nearly 5% of colorectal cancers are related to constitutional genetic abnormalities. In Lynch Syndrome (LS), the abnormality is a mutation of the deoxyribonucleic acid (DNA) repair system. The goal of this update is to update indications and surgical strategies for patients with LS. Different spectra of disease are associated with LS. The narrow spectrum includes cancers with a high relative risk: colorectal cancer (CRC), endometrial cancer, urinary tract cancers and small intestinal cancer. The broader spectrum includes ovarian tumors, glioblastoma, cutaneous tumors (keratoacanthomas and sebaceous tumors), biliary duct tumors, and gastric tumors. The clinical diagnosis of LS was initially based on the Amsterdam I and II Criteria published in the 1990s and subsequently on the revised Bethesda Criteria, which expanded the criteria and identified patients who should be screened for LS. For patients with LS, learned societies recommend early and regular endoscopic screening because of the high incidence of CRC, i.e., every one to two years from the age of 25 and then annually from the age of 40 or starting 10 years before the age of appearance of the youngest case of CRC in the family. Professional recommendations on prophylactic surgery to prevent cancers in patients with genetic predisposition were published in 2009 under the auspices of the French National Cancer Institute and are still current. There is no formal indication for prophylactic colectomy in LS. Numerous advances have been made in the understanding of LS, allowing a better knowledge of the prevalence of CRCs and associated cancers, with better endoscopic monitoring and a decrease in the prevalence and mortality of CRC.
Topics: Colectomy; Colonic Neoplasms; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Endoscopy, Gastrointestinal; Humans; Immunohistochemistry; Microsatellite Instability; Prophylactic Surgical Procedures; Quality of Life; Rectal Neoplasms
PubMed: 31445799
DOI: 10.1016/j.jviscsurg.2019.07.009 -
Clinical Gastroenterology and... Feb 2020Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable...
BACKGROUND & AIMS
Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features.
METHODS
We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables.
RESULTS
We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC.
CONCLUSIONS
Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Female; Humans; Microsatellite Instability; MutL Protein Homolog 1; Neoplastic Syndromes, Hereditary
PubMed: 31220642
DOI: 10.1016/j.cgh.2019.06.012 -
International Journal of Molecular... Jan 2021Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial... (Review)
Review
Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in , , , and , and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.
Topics: Carcinoma; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA-Binding Proteins; Genetic Predisposition to Disease; Humans; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Urothelium
PubMed: 33430305
DOI: 10.3390/ijms22020531 -
Gastroenterology Apr 2008
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Humans; Immunity, Cellular; T-Lymphocytes
PubMed: 18395102
DOI: 10.1053/j.gastro.2008.02.008 -
Cells Feb 2023Lynch syndrome (LS) is an inherited disorder in which affected individuals have a significantly higher-than-average risk of developing colorectal and non-colorectal...
Lynch syndrome (LS) is an inherited disorder in which affected individuals have a significantly higher-than-average risk of developing colorectal and non-colorectal cancers, often before the age of 50 years. In LS, mutations in DNA repair genes lead to a dysfunctional post-replication repair system. As a result, the unrepaired errors in coding regions of the genome produce novel proteins, called neoantigens. Neoantigens are recognised by the immune system as foreign and trigger an immune response. Due to the invasive nature of cancer screening tests, universal cancer screening guidelines unique for LS (primarily colonoscopy) are poorly adhered to by LS variant heterozygotes (LSVH). Currently, it is unclear whether immunogenomic components produced as a result of neoantigen formation can be used as novel biomarkers in LS. We hypothesise that: (i) LSVH produce measurable and dynamic immunogenomic components in blood, and (ii) these quantifiable immunogenomic components correlate with cancer onset and stage. Here, we discuss the feasibility to: (a) identify personalised novel immunogenomic biomarkers and (b) validate these biomarkers in various clinical scenarios in LSVH.
Topics: Humans; Middle Aged; Female; Colorectal Neoplasms, Hereditary Nonpolyposis; Biomarkers; Endometrial Neoplasms; Germ-Line Mutation
PubMed: 36766832
DOI: 10.3390/cells12030491