TY - JOUR
T1 - DNA Mismatch Repair Gene Variant Classification
T2 - Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
AU - on behalf of ANGELS Study
AU - Walker, Romy
AU - Mahmood, Khalid
AU - Como, Julia
AU - Clendenning, Mark
AU - Joo, Jihoon E.
AU - Georgeson, Peter
AU - Joseland, Sharelle
AU - Preston, Susan G.
AU - Pope, Bernard J.
AU - Chan, James M.
AU - Austin, Rachel
AU - Bojadzieva, Jasmina
AU - Campbell, Ainsley
AU - Edwards, Emma
AU - Gleeson, Margaret
AU - Goodwin, Annabel
AU - Harris, Marion T.
AU - Ip, Emilia
AU - Kirk, Judy
AU - Mansour, Julia
AU - Mar Fan, Helen
AU - Nichols, Cassandra
AU - Pachter, Nicholas
AU - Ragunathan, Abiramy
AU - Spigelman, Allan
AU - Susman, Rachel
AU - Christie, Michael
AU - Jenkins, Mark A.
AU - Pai, Rish K.
AU - Rosty, Christophe
AU - Macrae, Finlay A.
AU - Winship, Ingrid M.
AU - Buchanan, Daniel D.
N1 - Funding Information:
This project was funded by a National Health and Medical Research Council of Australia (NHMRC) project grant GNT1125269 (PI- Daniel Buchanan). D.D.B. is supported by an NHMRC Investigator grant (GNT1194896) and University of Melbourne Dame Kate Campbell Fellowship. R.W. is supported by the Margaret and Irene Stewardson Fund Scholarship and by the Melbourne Research Scholarship. P.G. is supported by the University of Melbourne Research Scholarship. M.A.J. is supported by an NHMRC Investigator grant (GNT1195099). The Colon Cancer Family Registry (CCFR, www.coloncfr.org, accessed on 6 October 2023) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following U.S. state cancer registries: AZ, CO, MN, NC, NH; and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada).
Funding Information:
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.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
KW - colorectal cancer
KW - DNA mismatch repair deficient crypts/glands
KW - DNA mismatch repair gene somatic mutations
KW - DNA mismatch repair gene variant classification
KW - endometrial cancer
KW - Lynch syndrome
KW - variant of uncertain significance
UR - http://www.scopus.com/inward/record.url?scp=85175452715&partnerID=8YFLogxK
U2 - 10.3390/cancers15204925
DO - 10.3390/cancers15204925
M3 - Article
C2 - 37894291
AN - SCOPUS:85175452715
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 20
M1 - 4925
ER -