Cancers (Oct 2023)
DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
- Romy Walker,
- Khalid Mahmood,
- Julia Como,
- Mark Clendenning,
- Jihoon E. Joo,
- Peter Georgeson,
- Sharelle Joseland,
- Susan G. Preston,
- Bernard J. Pope,
- James M. Chan,
- Rachel Austin,
- Jasmina Bojadzieva,
- Ainsley Campbell,
- Emma Edwards,
- Margaret Gleeson,
- Annabel Goodwin,
- Marion T. Harris,
- Emilia Ip,
- Judy Kirk,
- Julia Mansour,
- Helen Mar Fan,
- Cassandra Nichols,
- Nicholas Pachter,
- Abiramy Ragunathan,
- Allan Spigelman,
- Rachel Susman,
- Michael Christie,
- Mark A. Jenkins,
- Rish K. Pai,
- Christophe Rosty,
- Finlay A. Macrae,
- Ingrid M. Winship,
- Daniel D. Buchanan
Affiliations
- Romy Walker
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Khalid Mahmood
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Julia Como
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Mark Clendenning
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Jihoon E. Joo
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Peter Georgeson
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Sharelle Joseland
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Susan G. Preston
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Bernard J. Pope
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- James M. Chan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Rachel Austin
- Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4006, Australia
- Jasmina Bojadzieva
- Clinical Genetics Unit, Austin Health, Melbourne, VIC 3084, Australia
- Ainsley Campbell
- Clinical Genetics Unit, Austin Health, Melbourne, VIC 3084, Australia
- Emma Edwards
- Familial Cancer Service, Westmead Hospital, Sydney, NSW 2145, Australia
- Margaret Gleeson
- Hunter Family Cancer Service, Newcastle, NSW 2298, Australia
- Annabel Goodwin
- Cancer Genetics Department, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
- Marion T. Harris
- Monash Health Familial Cancer Centre, Clayton, VIC 3168, Australia
- Emilia Ip
- Cancer Genetics Service, Liverpool Hospital, Liverpool, NSW 2170, Australia
- Judy Kirk
- Hunter Family Cancer Service, Newcastle, NSW 2298, Australia
- Julia Mansour
- Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Hobart, TAS 7000, Australia
- Helen Mar Fan
- Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4006, Australia
- Cassandra Nichols
- Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA 6008, Australia
- Nicholas Pachter
- Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA 6008, Australia
- Abiramy Ragunathan
- Hunter Family Cancer Service, Newcastle, NSW 2298, Australia
- Allan Spigelman
- Cancer Genetics Department, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
- Rachel Susman
- Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD 4006, Australia
- Michael Christie
- Department of Medicine, Royal Melbourne Hospital, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia
- Mark A. Jenkins
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Rish K. Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
- Christophe Rosty
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- Finlay A. Macrae
- Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC 3052, Australia
- Ingrid M. Winship
- Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC 3052, Australia
- Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3000, Australia
- DOI
- https://doi.org/10.3390/cancers15204925
- Journal volume & issue
-
Vol. 15,
no. 20
p. 4925
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 performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
Keywords
- Lynch syndrome
- DNA mismatch repair gene variant classification
- DNA mismatch repair deficient crypts/glands
- colorectal cancer
- endometrial cancer
- variant of uncertain significance