Somatic mutations of DNA damage repair (DDR) genes in patients with epithelial ovarian cancer

Abstract

Objectives: Gene mutations are proved to be associated in epithelial ovarian cancer. The majority of researches focus on BRCA1/2 in ovarian serous carcinoma. The incidence of ovarian clear cell carcinoma and endometrioid carcinoma are estimated to be 15% respectively in East Asia, especially in Japan and Taiwan, which is far more prevalent than in the Western countries. However, the somatic gene mutations of DNA damage repair genes in ovarian clear cell carcinoma and endometrioid carcinoma is unclear. Methods: We investigated the somatic mutations of epithelial ovarian cancer patients using a panel containing DNA damage repair genes by next generation sequencing method. Totally 172 epithelial ovarian carcinoma patients, including 69 serous carcinoma, 39 endometrioid carcinoma and 64 clear cell carcinoma, were enrolled. Results: Totally 78 patients with DDR somatic gene mutations were noted, including 48 (69.6%) in serous carcinoma, 13 (33.3%) in endometrioid carcinoma and 17 (26.6%) in clear cell carcinoma. In 69 serous carcinoma patients, gene mutations were 39 TP53 (56.5%), 4 BRCA2 (5.8%), 4 RAD51C (5.8%), 3 MUTYH (4.3%), 3 ERCC8 (4.3%), 1 BRCA1 (1.4%), 1 BRIP1 (1.4%), 1 FANCG (1.4%), 1 RAD51D (1.4%), 1 MLH3 (1.4%), 1 MSH6 (1.4%), 1 OGG1 (1.4%), 1 XRCC6 (1.4%) and 1 ATM (1.4%). In 39 endometrioid carcinoma, gene mutations were 6 TP53 (15.4%), 5 ATM (12.8%), 3 MSH2 (7.7%), 2 MUTYH (5.1%), 2 MLH3 (5.1%), 2 RAD50 (5.1%), 1 BRCA2 (2.6%), 1 MSH6 (2.6%), 1 FANCC (2.6%), 1 FANCM (2.6%), 1 MRE11 (2.6%), 1 MLH1 (2.6%) and 1 MSH3 (2.6%). In 64 clear cell carcinoma, gene mutations were 6 MUTYH (9.4%), 3 TP53 (4.7%), 2 BRCA2 (3.1%), 2 ERCC8 (3.1%), 1 BRCA1 (1.6%), 1 FANCI (1.6%), 1 RAD50 (1.6%), 1 MLH1 (1.6%), 1 MLH3 (1.6%), 1 MSH6 (1.6%), 1 XRCC4 (1.6%), 1 POLD1 (1.6%), 1 CHEK2 (1.6%) and 1 BARD1 (1.6%). In homologous recombination repair genes, the percentage of somatic mutations was 15.9%, 7.7% and 6.3% for serous, endometrioid and clear cell carcinoma (p=0.154, chi-square test). In mismatch repair genes, the percentage of somatic mutations was 2.9%, 15.4% and 4.7% for serous, endometrioid and clear cell carcinoma respectively (p=0.003, chi-square test). In double strand break repair genes, the percentage of somatic mutations was 17.4%, 7.7% and 6.3% for serous, endometrioid and clear cell carcinoma (p=0.092, chi-square test). In single strand break repair genes, the percentage of somatic mutations was 13.0%, 20.5% and 15.6% for serous, endometrioid and clear cell carcinoma (p=0.591, chi-square test). In cell cycle regulation genes, the percentage of somatic mutations was 58.0%, 23.1% and 6.3% for serous, endometrioid and clear cell carcinoma (p Conclusions: The pattern of somatic gene mutations of DNA damage repair genes differs in the serous, endometrioid and clear cell carcinoma patients. Our findings could provide the basis of precision medicine strategy for ovarian cancer treatment.