Objectives Abnormalities in mismatch repair (MMR) gene may be the result of pathogenic germline (Lynch syndrome) and somatic mutations as well as epigenetic events. We aimed to examine the cause of MMR defects (MMRd) in non-serous/non-mucinous ovarian cancer (OC) through targeted mutational sequencing.

Methods Women with non-serous/mucinous OC (N = 215) were prospectively recruited from three cancer centers in Ontario, Canada. Tumors were assessed for MMR protein expression by immunohistochemistry. Matched MMRd tumor-normal samples were run on a custom NGS panel to identify germline and somatic mutations, copy number variants, rearrangements and promoter methylation in MMR and associated genes.

Results Of 215 women enrolled in our study, 185 (86%) had OC and 30 (14%) had synchronous OC and endometrial cancer. Twenty-eight (13%) cases were MMRd, 11 of which were synchronous. Using the NGS panel, Lynch syndrome (LS) was detected in 39% of MMRd cases (11/28; 7 OC and 4 synchronous): 7 MSH6, 2 MLH1, 1 PMS2, and 1 MSH2. An explanation for the observed MMR phenotype was available for 18/20 deficient cases, including 9/10 MLH1-/PMS2- (7 somatic methylation, 1 bi-allelic somatic deletion, 1 germline mutation), 0/1 PMS2-, 6/7 MSH6- (6 germline mutations) and 2/2 MSH2-/MSH6- (1 germline mutation, 1 bi-allelic somatic mutation). Concordance between clinical and research panel sequencing results was 90%.

Conclusions Use of our custom NGS panel allows for the streamlined assessment of hereditary and somatic causes of MMR deficiency in OC and may be an attractive screening strategy for LS in this population.