High-grade serous ovarian carcinoma (HG-SOC) is a poorly prognosed and lethal gynecological disease where only 30% of patients survive beyond five years after initial pathologic diagnosis. However, the heterogeneity of HG-SOC tumors meant that patients often respond differently despite similar clinical intervention. Therefore, identification of novel molecular tumor subtypes/classes, tumor-driving mutations and prognostically significant patient subgroups could provide improvement in clinical management as well as facilitate our understanding of this complex disease and subsequent design of targeted personalized therapeutics. In this work, we performed integrative bioinformatics analyses of mutational and clinical data of HG-SOC patients from The Cancer Genome Atlas(TCGA) and aim to identify the driver genes and their mutations with emphasis on their prognostic significance and molecular functions which could be used as molecular targets for personalization of HG-SOC therapeutics. We identified a 27-gene mutagenesis signature from the study of 334 HG-SOC patients, and our results indicated that the use of this signature can significantly stratify a subgroup of 24 patients with very poor overall survival prognosis (p-value=3.8E-09); all these 24 patients did not survive beyond five years after initial diagnosis. Among these 27 genes, physiological functions such as kinase activity or ATP binding were enriched, and suggest that targeting of these specific cellular programs could be employed to modify tumors' response to therapy and patients' overall survival time. Mutations in CHEK2, RPS6KA2 and MLL4 strongly co-occurred in tumor cells of the poor prognosis patient subgroup which in turn, were under-represented with mutations of BRCA1 or BRCA2. CHEK2 mutations were significantly correlated with poor patient prognosis (p-value=0.00012) and poor response to therapy (p-value =0.046). In 22 of the 24 HG-SOC patients, CHEK2 mutations occurred within a nuclear localization signal (NLS). Results from computational modeling, coupled with literature support, suggest that mutations within the NLS locus could potentially inhibit nuclear import of the Chk2 protein and lead to reduction of Chk2 protein levels in the nucleus. Our findings revealed a previously uncharacterized genetic subtype of HG-SOCs hallmarked with the 27 mutated genes which could result in the functional aberrations in interactions and pathways associated with the genes, possibly leading to very poor prognosis and chemotherapeutic response. We identified a cluster of mutations in the final exon of CHEK2 that selectively predict poor prognosis allowing us to stratify patients that might benefit from therapeutic strategies that target aberrant Chk2 oncogenic signaling in HG-SOC progression. Experiments that will validate the impact of Chk2 mutations are currently underway.

Citation Format: Ghim Siong Ow, Anna V. Ivshina, Gloria Fuentes, Vladimir A. Kuznetsov. CHEK2 mutation is an adverse prognostic survival factor for patients diagnosed with high-grade serous ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3815. doi:10.1158/1538-7445.AM2014-3815