Germline and somatic genetic profiles of epithelial ovarian carcinoma patients sensitive and resistant to platinum derivatives estimated by targeted DNA sequencing
Abstract
Introduction/Background Epithelial ovarian carcinoma (EOC) is among the most fatal gynecological malignancies in the world. This is due to the late diagnosis and frequent therapy resistance. This study aimed to provide target DNA sequencing of 144 genes with potential involvement in resistance of EOC in surgically resected patients. Results were associated with clinical data and survival and validated using data from the whole exome sequencing (WES) and databases.
Methodology Target DNA sequencing of 144 gene panel in 48 pairs of EOC tumor and blood samples. The examined preselected 144 target gene panel was composed of the most important oncodriver genes in EOC, interacting genes as well as genes associated with the risk of EOC and resistance development. Comparison with WES of the next 50 blood and tumor tissue sample pairs, evaluation of platinum resistance status, and complete follow up. Validation of crucial variants using TCGA and GENIE datasets.
Results Germline genetic profile revealed as the most mutated genes RAD51B (20%), BRCA1/2 (14/9%) a DNAH14 (11%). Analysis of somatic variants revealed as the most mutated genes TP53 (98%), CSMD1/2/3 (19/21/35%), and CFTR (23%). Mutation exclusivity was found for germline variants in RAD51B (p=0.002), BRCA1 (0.015) and DNAH14 (0.036) and somatic variants in TP53. High TP53 mutation rate in patients with high grade serous ovarian carcinoma was confirmed by WES and TCGA and/or GENIE datasets analysis. In contrast to WES, TP53 splicing mutations were covered to a higher extent by targeted sequencing.
Conclusion Taken together, we assessed specific germline and somatic profiles of EOC patients using targeted DNA sequencing with potential to be associated with sensitivity to therapy especially in TP53 gene regions.
Disclosures This study was supported by running projects of the Czech Health Research Council grant no. NU20-09-00174 and Cooperatio program no. 207035, 'Maternal and Childhood Care' by 3rd Faculty Medicine, Charles University.