Germline and somatic variants in candidate therapy resistance biomarker genes in ovarian cancer by targeted sequencing

High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological carcinomas in the world. This is due to the late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by targeted DNA sequencing and identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Targeted sequencing results were compared with those from whole exome sequencing of a similar set 35 HGSC patients. Candidate somatic variants in TP53 were also validated using a targeted sequencing GENIE dataset of 1209 HGSC samples. Our high-coverage targeted approach showed higher prevalence of high impact somatic and germline mutations, mainly splice site variants of TP53, when compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations. We show that targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future analyses should include intersections between the expression and mutational profile of other crucial genes and explore targeting the p53 pathway based on specific mutation types.