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. 2021 Jan;160(1):161-168.
doi: 10.1016/j.ygyno.2020.10.012. Epub 2020 Oct 21.

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients

Heather Hampel  1 , Rachel Pearlman  2 , Albert de la Chapelle  3 , Colin C Pritchard  4 , Weiqiang Zhao  5 , Dan Jones  5 , Ahmet Yilmaz  5 , Wei Chen  5 , Wendy L Frankel  5 , Adrian A Suarez  5 , Casey Cosgrove  6 , Floor Backes  6 , Larry Copeland  6 , Jeffrey Fowler  6 , David O'Malley  6 , Ritu Salani  7 , Joseph P McElroy  8 , Peter P Stanich  2 , Paul Goodfellow  6 , David E Cohn  6
Affiliations

Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients

Heather Hampel et al. Gynecol Oncol. 2021 Jan.

Abstract

Objective: Lynch syndrome is the most common cause of inherited endometrial cancer, attributable to germline pathogenic variants (PV) in mismatch repair (MMR) genes. Tumor microsatellite instability (MSI-high) and MMR IHC abnormalities are characteristics of Lynch syndrome. Double somatic MMR gene PV also cause MSI-high endometrial cancers. The aim of this study was to determine the relative frequency of Lynch syndrome and double somatic MMR PV.

Methods: 341 endometrial cancer patients enrolled in the Ohio Colorectal Cancer Prevention Initiative at The Ohio State University Comprehensive Cancer Center from 1/1/13-12/31/16. All tumors underwent immunohistochemical (IHC) staining for the four MMR proteins, MSI testing, and MLH1 methylation testing if the tumor was MMR-deficient (dMMR). Germline genetic testing for Lynch syndrome was undertaken for all cases with dMMR tumors lacking MLH1 methylation. Tumor sequencing followed if a germline MMR gene PV was not identified.

Results: Twenty-seven percent (91/341) of tumors were either MSI-high or had abnormal IHC indicating dMMR. As expected, most dMMR tumors had MLH1 methylation; (69, 75.8% of the dMMR cases; 20.2% of total). Among the 22 (6.5%) cases with dMMR not explained by methylation, 10 (2.9% of total) were found to have Lynch syndrome (6 MSH6, 3 MSH2, 1 PMS2). Double somatic MMR PV accounted for the remaining 12 dMMR cases (3.5% of total).

Conclusions: Since double somatic MMR gene PV are as common as Lynch syndrome among endometrial cancer patients, paired tumor and germline testing for patients with non-methylated dMMR tumor may be the most efficient approach for LS screening.

Keywords: Cancer; Double somatic; Endometrial; Lynch syndrome; Mismatch repair; Neoplasm; Somatic.

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Conflict of interest statement

Declaration of Competing Interest Professor Hampel is on the scientific advisory board for Genome Medical, InVitae Genetics, and Promega, and has had research support from Myriad Genetics Laboratories, Inc. Ms. Pearlman has had research support from Myriad Genetics Laboratories, Inc. Dr. Pritchard consults for Promega and AstraZeneca. Dr. Stanich receives research support from Emtora Biosciences, Janssen Pharmaceuticals Inc., Pfizer Inc. and the PTEN Research Foundation. Drs. Backes, Chen, Cohn, Copeland, Cosgrove, de la Chapelle, Frankel, Fowler, Jones, McElroy, O'Malley, Salani, Suarez, Yilmaz, and Zhao have no conflicts of interest to disclose.

Figures

Fig. 1.
Fig. 1.
Endometrial cancer study schema.
See this image and copyright information in PMC

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