Journal article
DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
R Walker, K Mahmood, J Como, M Clendenning, JE Joo, P Georgeson, S Joseland, SG Preston, BJ Pope, JM Chan, R Austin, J Bojadzieva, A Campbell, E Edwards, M Gleeson, A Goodwin, MT Harris, E Ip, J Kirk, J Mansour Show all
Cancers | MDPI | Published : 2023
Abstract
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also perform..
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Awarded by National Institutes of Health
Funding Acknowledgements
The authors thank members of the Colorectal Oncogenomics Group and members from the Genomic Medicine and Family Cancer Clinic for their support of this manuscript. We thank the participants and staff from the ANGELS study and from the Australasian site of the Colon Cancer Family Registry (ACCFR), in particular Maggie Angelakos, Samantha Fox, and Allyson Templeton for their support of this manuscript. The authors thank the Australian Genome Research Facility for their collaboration on this project. The CCFR graciously thanks the generous contributions of their 42,505 study participants, dedication of study staff, and the financial support from the U.S. National Cancer Institute, without which this important registry would not exist. The content of this manuscript does not necessarily reflect the views or policies of the NIH or any of the collaborating centers in the CCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR.