Lynch syndrome (LS) is a common cancer syndrome that is inherited in an autosomal dominant manner. Its pathogenesis is thought to be closely related to germline mutations of mismatch repair (MMR) genes such as the MLH1, MSH2, PMS2 and MSH6 genes. This study identifies a Chinese family with LS clinically diagnosed according to the Amsterdam II criteria. In these patients, immuno-histochemical staining showed negative MSH6 expressions but positive MLH1, MSH2, and PMS2 expressions. In order to further explore the molecular biology of this LS family, we used targeted next-generation sequencing (NGS) and Multiplex ligation dependent probe amplification (MLPA) to identify the mutation and verify the authenticity of the mutation in 15 family members. For NGS, two panels have been used, one is of MLH1, MSH2, PMS2 and MSH6 genes, the other one is of 139 cancer genetic susceptibility genes. And for the large deletions/duplications can also be identified by NGS panel, an adjusted data analysis strategy of NGS has been used. As a result, we identified a novel heterozygous large deletion in MSH6 gene that was found to be co-segregated among affected family members. This deletion results in the loss of a 3246 bp-sized fragment in MSH6 gene exons 5-9 which represents the coding regions of the MSH6 ATPase domain. This novel mutation has yet to be documented in the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database. This mutation resulted in MSH6 protein losing gene mismatch repair function, and further caused the microsatellite instable. We speculate that this mutation may significantly impact MMR function through impaired ATP domain function. Theoretically, this proband would likely benefit from PD-1 immune check-point blockade therapy, but conversely, we observed that tumors appeared to rapidly progress after 4 sessions of anti-PD-1 treatment. Further studies to validate the effectiveness of anti-PD-1 treatments in carriers of this mutation are necessary.
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http://dx.doi.org/10.1016/j.gene.2019.04.011 | DOI Listing |
Biol Res
December 2024
Unidad de Innovación en Prevención y Oncología de Precisión Centro Oncológico, Facultad de Medicina, Unidad de Innovación en Prevención y Oncología de Precisión Universidad Católica del Maule, Talca, 3480094, Chile.
Background: Breast cancer is a leading cause of cancer-related mortality worldwide, with hereditary forms accounting for approximately 10% of cases. In Chile, significant gaps exist in genetic counseling and testing, particularly within the public health system. This study presents the implementation and outcomes of the first regional hereditary cancer program in the Maule region of Chile, aimed at improving detection and management of hereditary breast cancer.
View Article and Find Full Text PDFFam Cancer
December 2024
Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome whereby the lifetime risk of developing gastrointestinal and genitourinary cancers rises by to over 50%. It is caused by heterozygous variants in the DNA mismatch repair genes- MLH1, MSH2, MSH6 and PMS2, with the majority detected in MLH1 and MSH2. Recurrently observed LS-associated variants in apparently unrelated individuals have either arisen de novo in different families due to mutation hotspots or are inherited from a common ancestor (founder) that lived several generations back.
View Article and Find Full Text PDFCancer Genet
December 2024
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:
Impairment of DNA mismatch repair function in neoplasms can be assessed by DNA-based methods to assess for high microsatellite instability (MSI-High) or immunohistochemical (IHC) analysis to assess for deficiency of mismatch repair proteins (dMMR). Neoplasms with mismatch repair deficiency often have high tumor mutational burden (TMB-High). MSI-High, dMMR, and TMB-High are all histology agnostic biomarkers for potential therapy using immune checkpoint inhibitors (ICI).
View Article and Find Full Text PDFPlant Cell
December 2024
Unidad de Genómica Avanzada, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Irapuato, Gto, México.
The widely distributed MutS gene family functions in recombination, DNA repair, and protein translation. Multiple evolutionary processes have expanded this gene family in plants relative to other eukaryotes. Here, we investigate the origins and functions of these plant-specific genes.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Department of Molecular Genetics and The National Tumour Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Centre, Ráth György u. 7-9, 1122 Budapest, Hungary.
Using multigene panel testing for the diagnostic evaluation of patients with hereditary breast and ovarian cancer (HBOC) syndrome often identifies clinically actionable variants in genes with varying levels of penetrance. High-penetrance genes (, , , , , , ) inform specific clinical surveillance and therapeutic decisions, while recommendations for moderate-penetrance genes (, , , , , , , , , , , ) are more limited. A detailed disease history, including pedigree data, helps formulate the most appropriate and personalised management strategies.
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