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Constitutional Mismatch Repair Deficiency Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Human cells are exposed to both extrinsic (e.g., ultraviolet radiation, carcinogens, and oxidative stress, etc.) and intrinsic (e.g., replication error) factors that can damage DNA, impair gene expression, and induce genomic instability and mutagenesis. To maintain stability and prevent transmission of mutations to progeny, human cells have evolved a number of mechanisms to repair damaged DNA. Of these, DNA mismatch repair genes play a vital role in repairing mistakes that remain after DNA polymerases replicate DNA.
Neoplasia
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Lynch syndrome, which is associated with colorectal adenocarcinoma in both sexes (previously called hereditary non-polyposis colorectal cancer) and endometrial carcinoma in women, involves defective DNA mismatch repair (see Chapter 5). The DNA mismatch repair pathway detects mismatches, where the nucleotides on complementary DNA strands do not match correctly (e.g. T:G, normally A:T, C:G) and excises the recently replicated mismatched base. Mismatch repair also detects and repairs insertion or deletion loops in repetitive sequences (e.g. AAAAAA… or CACACA… known as microsatellites) and failure to do this leads to the accumulation of microsatellites that vary in length and are said to be unstable; microsatellite instability is an indication of defective DNA mismatch repair in Lynch syndrome tumours. Around 13% sporadic colorectal cancers can acquire defective mismatch repair via silencing of expression (by promoter hypermethylation) of MLH1 (one of the two major mismatch repair genes, along with MSH2).
Colorectal cancer syndromes
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause the common autosomal dominant cancer syndrome Lynch syndrome. Although colorectal cancer is a major part of Lynch syndrome, risks for cancers of the endometrium, ovary and other organs are also high. Historically, families with Lynch syndrome were usually identified because of their histories of early onset-cancers and the occurrence of multiple cancers in individual family members. Increasingly, however, cases are being identified by pathology services through the molecular characteristics of tumours that in Lynch syndrome show a form of genetic instability termed microsatellite instability (MSI) and loss of expression of MMR protein expression.
Combining inhibition of immune checkpoints and PARP: rationale and perspectives in cancer treatment
Published in Expert Opinion on Therapeutic Targets, 2022
Martina Catalano, Luigi Francesco Iannone, Federica Cosso, Daniele Generali, Enrico Mini, Giandomenico Roviello
Mismatch repair consists of DNA mismatch repair (MMR) systems that involve proteins that recognize and repair erroneous insertion, deletion, and mis-incorporation of bases caused by DNA polymerase during the DNA replication [10]. In non-tumoral cells, the repair system is formed by four main proteins: MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and Post Meiotic Segregation increased 2 (PMS2) [10]. Germinal and/or somatic deleterious variants of these proteins lead to the failure and inactivation of the MMR system with a consequent accumulation of high rate of mutations, mainly in microsatellites, detectable as microsatellite instability (MSI) [11]. Therefore, the instability of microsatellites represents the molecular phenotype of the DNA repair system deficit. Microsatellites also defined as short tandem repeats (STR) or Simple Sequence Repeat (SSRs), are short repeating sequences of 1–6 nucleotides [11].
Confirmation of Xp22.11 Duplication as a Germline Susceptibility Alteration in a Wilms Tumor Arising in Horseshoe Kidney
Published in Fetal and Pediatric Pathology, 2022
Hui-fang Zhou, Ina E. Amarillo, Stacy Snyder, Jorge L. Granadillo, Christopher J. O’Conor, Patrick Dillon, David Wilson, Frederick S. Huang, Louis P. Dehner, Mai He
The PMS2 pathogenic variant found in our patient is known to cause Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) syndrome. So far there has been very few studies regarding the association of DNA mismatch repair (MMR), Lynch (HNPCC) syndrome, and Wilms tumor [16–18]. Poley et al reported that carriage of biallelic MMR gene defects can be associated with multiple malignancies in childhood that may differ from the standard spectrum of HNPCC tumor types [16]. Diniz and colleagues studied 45 cases of Wilms tumor for microsatellite instability (MSI) by PCR and MMR protein immunohistochemistry (IHC) panel including MLH1, PMS2, MSH2, or MSH6 [17]. Their results showed that 13.3% of the WT cases had MSI and 42.2% of the cases had loss of protein expression by IHC. These findings suggest that MMR genes may play an important role in the development of WT via different pathways [17].
Triumph against cancer: invading colorectal cancer with nanotechnology
Published in Expert Opinion on Drug Delivery, 2021
Preksha Vinchhi, Mayur M. Patel
Approximately, 70–80% of CRCs are sporadic which typically results from mutations that affect Wnt/β catenin signaling pathway. Remaining 20–30% of CRC cases account for hereditary CRC which includes hereditary nonpolyposis CRC/Lynch syndrome (2–4%), familial adenomatous polyposis (FAP) (1%) and MUTYH associated polyposis (MAP) (1%). Lynch syndrome is caused because of mutation in the genes involved in DNA mismatch repair, e.g. MutL homolog 1(MLH 1), MutS protein homolog 2(MSH 2), MutS protein homolog 6 (MSH 6), Mismatch repair endonuclease (PMS2) and epithelial cell adhesion molecule (EpCAM). Whereas FAP is caused by mutations in adenomatous polyposis coli (APC – a tumor suppressor gene). Juvenile polyposis, peutz jeghers disease, muir torre syndrome, Cowden disease are some of the rare hereditary syndromes [13].