Study on Homologous Recombination Aberrations in Ovarian Cancer

Ovarian cancer is one of the deadliest gynecologic malignancies. The 5-year overall survival rates of ovarian cancer are poor despite improvement in treatment. With the advent of next generation sequencing, diverse genetic alterations have been found in ovarian cancer. BRCA1/2 mutations could be detected in blood (germline mutations, 15-20%) and tissues (somatic mutations, 5-10%), regardless of family history in patients with ovarian cancer. Therapies that target DNA repair proteins might have a tailored treatment option for the various histologic subtypes. Various poly ADP ribose polymerase inhibitor (PARPi) have shown activity in combination with chemotherapy. Our previous data showed that the somatic and germline BRCA1/2 mutation rates are 8.7% and 17%, respectively, in 46 patients with serous ovarian cancer. One-third of the pathogenic BRCA1/2 mutations occurred only in tumor tissues. Notably, five novel pathogenic mutations were identified in Taiwan, including four somatic variants (BRCA1 p.S242fs, BRCA1 p.F989fs, BRCA1 p.G1738fs, and BRCA2 p.D1451fs) and a germline variant (BRCA2 p.E260fs). Patients with ovarian cancers that have mutations in homologous recombination deficiencies (HRD) might respond to PARPi based on synthetic lethality. Clinical significance of PARPi in a broader group of ovarian cancer patients in Taiwan with HRD needs further scrutinity since BRCA1/2 germline and somatic mutations were associated with a fraction of ovarian cancer cases only. Genes involved in the HR pathway of DNA repair (BRCAness) and epigenetic silencing added up to the HRD to as much as half of high-grade serous ovarian cancers in The Cancer Genome Atlas. Hence, translational research could be extended to the detection and determination of other BRCAness genes/homologous deficient genes in blood/tumor samples of ovarian cancer. Addition of predictive biomarker HRD score might be integrated into the therapeutic opportunities of PARPi therapy in ovarian cancer patients. In the 3-year project, we aim to: 1. To investigate BRCAness genes in ovarian cancer; 2. To determine HRD score and correlate with clinicopathological factors, and the possibility of HRD score to serve as a prediction marker of using PARPi; 3. To establish culture system for primary cancer cells and perform functional assays for determining homologous deficiencies in primary ovarian cancer cells.

Project ID:PC10608-1472
External Project ID:MOST106-2314-B182-053-MY2