Microsatellite instability in colorectal cancer: overview of its clinical significance and novel perspectives.

This article, an overview of the expanding role of MSI in CRC, covers its clinical significance, the available data on molecular profiling, novel perspectives on MSI testing, biomarkers in MSI-H CRC, immunotherapy resistance, and novel immunotherapy strategies. PMID: 30543589 [PubMed - in process]
Source: Clinical Advances in Hematology and Oncology - Category: Cancer & Oncology Tags: Clin Adv Hematol Oncol Source Type: research

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Abstract MMR-deficient colorectal cancers (dMMR CRC) are characterized by the expression of highly-immunogenic neoantigen peptides, which stimulate lymphocytic infiltration as well as up-regulation of inflammatory cytokines. These features are key to understanding why immunotherapy (specifically PD-1 and/or CTLA-4 checkpoint blockade) has proved to be highly effective for the treatment of patients with advanced dMMR CRC. Importantly, pre-clinical studies also suggest that this correlation between potent tumor neoantigens and the immune microenvironment is present in early (pre-malignant) stages of dMMR colorectal ...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Authors: Duraturo F, Liccardo R, De Rosa M, Izzo P Abstract Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The LS-associated cancer types include carcinomas of the endometrium, small intestine, stomach, pancreas and biliary tract, ovary, brain, upper urinary tract and skin. The criteria for the clinical diagnosis of LS and the procedures of the genetic testing for identification of pathogenetic ...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
AbstractLynch 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,...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
Abstract Microsatellites are short tandem repeat DNA sequences of one to tetra base pairs distributed throughout the human genome, both in coding and non-coding regions. Owing to their repeated structure, microsatellites are particularly prone to replication errors that are normally repaired by the Mismatch Repair (MMR) system. MMR is a very highly conserved cellular process, involving many proteins, resulting in the identification, and subsequent repair of mismatched bases, likely to have arisen during DNA replication, genetic recombination or chemical or physical damage. Proteins within the MMR system include ML...
Source: Acta Bio-Medica : Atenei Parmensis - Category: General Medicine Authors: Tags: Acta Biomed Source Type: research
te; T Abstract 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 (microsate...
Source: Bulletin du Cancer - Category: Cancer & Oncology Authors: Tags: Bull Cancer Source Type: research
In this study, we employed the combination of germline testing and tumor mutational assessment to help discern the clinical relevance of VUS and guide immunotherapeutic decisions. KEY POINTS: A clinical dilemma arises when genomic testing yields variants of uncertain significance (VUS).Germline VUS were identified in two patients with gastrointestinal malignancies, but only one patient had a second-hit mutation in a mismatch repair gene leading to mismatch repair deficiency that conferred response to immunotherapy.The combination of germline testing along with tumor mutational assessment can help discern the clinical ...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
Introduction: Molecular evaluation of KRAS, NRAS and BRAF mutation has become an important part in colorectal carcinoma evaluation as their alterations determine the therapeutic response to anti-EGFR therapy and prognosis. MMR deficiency is important for identification of Lynch syndrome families and it has now become an important biomarker of response to immunotherapy in metastatic CRC. The aim of this study is to investigate the distribution of these mutations by tumor localization and to determine the prevalence of MMR deficiency in metastatic colorectal cancer.
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsTherefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1.
Source: International Journal of Clinical Oncology - Category: Cancer & Oncology Source Type: research
CONCLUSIONS: Therefore, compared with Lynch-syndrome-associated cancers, sporadic MSI cancers are more frequently solid, poorly differentiated medullary cancers that express PD-L1. PMID: 29327160 [PubMed - as supplied by publisher]
Source: Clinical Colorectal Cancer - Category: Cancer & Oncology Authors: Tags: Int J Clin Oncol Source Type: research
ConclusionsdMMR biliary tract cancers associated with LS are rare but long-term outcomes may be more favorable than contemporaneous cohorts of non-Lynch-associated cholangiocarcinomas. Given the emerging promise of immunotherapy for patients with dMMR malignancies, tumor testing for dMMR followed by confirmatory germline testing should be considered in patients with BTC and a personal history of other LS cancers.
Source: Journal of Gastrointestinal Cancer - Category: Cancer & Oncology Source Type: research
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