Prevalence of Lynch Syndrome in Middle Eastern Women with Mismatch Repair Deficient Ovarian Cancer

Author(s): Abdul K Siraj, Rong Bu, Sandeep Kumar Parvathareddy, Kaleem Iqbal, Saud Azam, Padmanaban Annaiyappanaidu, Nabil Siraj, Ingrid G Victoria, Wael Haqawi, Mohamed Alhamed, Ismail A Al-Badawi, Fouad Al-Dayel, Khawla S Al-Kuraya

Objective: Microsatellite instability (MSI) is a hallmark of Lynch Syndrome (LS). This study aims to determine the prevalence of LS and the optimal diagnostic method in women from Middle Eastern ethnicity with newly diagnosed epithelial ovarian cancer (EOC).

Methods: Women newly diagnosed with primary EOC (n=424) were retrospectively assessed for deficient mismatch repair (dMMR) by immunohistochemistry (IHC). All cases suggestive of LS by IHC underwent germline mutation testing in MMR pathway and additional exome sequencing.

Results: 2.8% (12/424) of EOCs showed mismatch repair deficiency by IHC. MSH2/MSH6 protein loss was detected in five cases (41.7%), only MSH6 protein loss in four cases (33.3%) and MLH1/PMS2 protein loss in three cases (25.0%). None of the three cases of MLH1 loss showed MLH1 promoter hypermethylation. Two cases (16.7%) were confirmed to have LS. No double heterozygous somatic mutations were detected. Germline pathogenic variants in high penetrance OC susceptibility genes were seen in two cases: one with BRCA2 and another with ATM germline mutation. In addition, we found five cases harboring variants of uncertain signifycance (VUS) in other hereditary genes.

Conclusions: This is the first comprehensive study in a Saudi Arabian cohort of EOC screened for LS, which revealed LS prevalence of 2.8%. Although LS was identified in only two of 12 dMMR EOCs, an additional seven cases showed either pathogenic mutations or VUS, accounting for 75% of dMMR cases. Hence, our findings expand the mutational spectrum of dMMR and LS-related genes, which is important to define the most effective strategy for identification, prevention and therapy for Middle Eastern EOC LS.