Large germline next generation (NGS) sequencing panel of uterine serous carcinoma.

Abstract

e13106 Background: Genetic predisposition to uterine serous carcinoma (USC) remains unclear and has been related to Lynch Syndrome (LS) and BRCA1/2 mutations. Wide NGS panels for this condition are starting to be implemented and data remain scarce. Methods: Consecutive USC were identified from a prospective endometrial cancer database (ECD) in a single institution. Clinical information including stage, follow-up, a three-generation pedigree, Microsatellite Instability (MSI) with 8 markers and the Mismatch Repair Protein (MMRPro) staining status, was retrieved from the ECD. Germline genetic testing was performed using a commercially available NGS panel including 80 familial cancer genes (Onco-GeneSGKit) on a MiSeq sequencer. Pathogenic or likely pathogenic variants were confirmed by Sanger sequencing. Results: Twenty-one women out of a total of 150 (14%) cases contained in the ECD were diagnosed with a USC. Median age was 65 (40-84 yo), median Body Mass Index of 26 (19-40), and histologically 18 were defined as pure and 3 as mixed USC. FIGO 2009 stages were I/II and III/IV in 42% and 58% of cases respectively. Adjuvant Chemotherapy (CT) was administered to 76%. MSI-High and MMRPro loss was described in 5%, 19% fulfilled Bethesda criteria, 23% had previous breast cancer and 5% personal Lynch related cancer history, 28% presented with pathological features of Lynch Syndrome such as dedifferentiation, Tumor Infiltrating Lymphocytes (14%), peritumoral lymphocytes or lower uterine location (14%). A median of 5 [range: 2-8] genetic alterations (pathogenic, variants of uncertain significance (VUS) and not described) per patient were observed, including 3 (14.3%) pathogenic mutations, 18 VUS and 43 not described. Among the three pathogenic mutations one was in MSH6 (p.Glu255Ter), another one in DKC1 (p.S280A) and the last one in the recessive gene MUTYH (p.Glu466del). VUS were detected in 57% of cases among 12 different genes: ATM (n = 3), AXIN2 (n = 2), BARD1 (N = 2), RAD50 (n = 2), RET (n = 2) and one case each of BMPR1A, BRIP1, CHEK2, MLH1, MSH6, SLX4 and TSC2. Conclusions: In our series 14% of USC harbored mutations in cancer predisposition genes.VUS are as high as 57% and represent a clinical challenge.