Compound heterozygous MSH3 germline variants and associated tumor somatic DNA mismatch repair dysfunction

Minoru Koi; Brandie H Leach; Sarah McGee; Stephanie S Tseng-Rogenski; Carol A Burke; John M Carethers

doi:10.1038/s41698-024-00511-2

Compound heterozygous MSH3 germline variants and associated tumor somatic DNA mismatch repair dysfunction

NPJ Precis Oncol. 2024 Jan 19;8(1):12. doi: 10.1038/s41698-024-00511-2.

Authors

Minoru Koi^{1

2}, Brandie H Leach^{3

4}, Sarah McGee^{3

4}, Stephanie S Tseng-Rogenski¹, Carol A Burke^{4

5}, John M Carethers^{6

7}

Affiliations

¹ Division of Gastroenterology & Hepatology, Department of Internal Medicine, and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
² Division of Gastroenterology & Hepatology, Department of Medicine, and Moores Cancer Center, University of California at San Diego, San Diego, CA, USA.
³ Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Cleveland Clinic, Cleveland, OH, USA.
⁵ Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, OH, USA.
⁶ Division of Gastroenterology & Hepatology, Department of Internal Medicine, and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. jcarethers@ucsd.edu.
⁷ Division of Gastroenterology & Hepatology, Department of Medicine, and Moores Cancer Center, University of California at San Diego, San Diego, CA, USA. jcarethers@ucsd.edu.

Abstract

We describe here an individual from a fourth family with germline compound heterozygous MSH3 germline variants and its observed biological consequences. The patient was initially diagnosed with invasive moderately-differentiated adenocarcinoma of the colon at the age of 43. Germline multigene panel testing revealed a pathogenic variant MSH3 c.2436-1 G > A and a variant of (initial) uncertain significance MSH3 c.3265 A > T (p.Lys1089*). Germline genetic testing of family members confirm the variants are in trans with the c.2436-1 G > A variant of paternal and the c.3265 A > T variant of maternal origin. Tumor DNA exhibits low levels of microsatellite instability and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). Tissue immunohistochemical staining for MSH3 demonstrated variant MSH3 protein is present in the cytoplasm and cell membrane but not in the nucleus of normal and tumor epithelial cells. Furthermore, variant MSH3 is accompanied by loss of nuclear MSH6 and a reduced level of nuclear MSH2 in some tumor cells, suggesting that the variant MSH3 protein may inhibit binding of MSH6 to MSH2.

Grants and funding

R01 CA258519/CA/NCI NIH HHS/United States