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; ANGELS Study

doi:10.3390/cancers15204925

DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands

Cancers (Basel). 2023 Oct 10;15(20):4925. doi: 10.3390/cancers15204925.

Authors

Romy Walker^{1

2}, Khalid Mahmood^{1

2

3}, Julia Como^{1

2}, Mark Clendenning^{1

2}, Jihoon E Joo^{1

2}, Peter Georgeson^{1

2}, Sharelle Joseland^{1

2}, Susan G Preston^{1

2}, Bernard J Pope^{1

2

3}, James M Chan^{1

2}, Rachel Austin⁴, Jasmina Bojadzieva⁵, Ainsley Campbell⁵, Emma Edwards⁶, Margaret Gleeson⁷, Annabel Goodwin^{8

9}, Marion T Harris¹⁰, Emilia Ip¹¹, Judy Kirk⁷, Julia Mansour¹², Helen Mar Fan⁴, Cassandra Nichols¹³, Nicholas Pachter^{13

14

15}, Abiramy Ragunathan⁷, Allan Spigelman^{8

16

17}, Rachel Susman⁴, Michael Christie^{18

19}, Mark A Jenkins^{2

20}, Rish K Pai²¹, Christophe Rosty^{1

2

22

23}, Finlay A Macrae^{24

25

26}, Ingrid M Winship^{24

26}, Daniel D Buchanan^{1

2

24}; ANGELS Study

Affiliations

¹ 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.
² 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.
³ Melbourne Bioinformatics, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia.
⁴ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia.
⁵ Clinical Genetics Unit, Austin Health, Melbourne, VIC 3084, Australia.
⁶ Familial Cancer Service, Westmead Hospital, Sydney, NSW 2145, Australia.
⁷ Hunter Family Cancer Service, Newcastle, NSW 2298, Australia.
⁸ Cancer Genetics Department, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
⁹ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia.
¹⁰ Monash Health Familial Cancer Centre, Clayton, VIC 3168, Australia.
¹¹ Cancer Genetics Service, Liverpool Hospital, Liverpool, NSW 2170, Australia.
¹² Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Hobart, TAS 7000, Australia.
¹³ Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA 6008, Australia.
¹⁴ Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA 6009, Australia.
¹⁵ School of Medicine, Curtin University, Perth, WA 6102, Australia.
¹⁶ St Vincent's Cancer Genetics Unit, Sydney, NSW 2010, Australia.
¹⁷ Surgical Professorial Unit, UNSW Clinical School of Clinical Medicine, Sydney, NSW 2052, Australia.
¹⁸ Department of Medicine, Royal Melbourne Hospital, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia.
¹⁹ Department of Pathology, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia.
²⁰ Centre for Epidemiology and Biostatistics, School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia.
²¹ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
²² Envoi Specialist Pathologists, Brisbane, QLD 4059, Australia.
²³ School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia.
²⁴ Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, VIC 3052, Australia.
²⁵ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia.
²⁶ Department of Medicine, Melbourne Medical School, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC 3052, Australia.

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: DNA mismatch repair deficient crypts/glands; DNA mismatch repair gene somatic mutations; DNA mismatch repair gene variant classification; Lynch syndrome; colorectal cancer; endometrial cancer; variant of uncertain significance.

Abstract

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