Clinicopathological and functional significance of XRCC1 expression in ovarian cancer

Abstract

X-ray repair cross-complementing gene 1 (XRCC1) is essential for DNA base excision repair, single strand break repair and nucleotide excision repair. We investigated clinicopathological and functional significance of XRCC1 expression in ovarian cancers. XRCC1 protein expression was evaluated in 195 consecutive human ovarian cancers and correlated with clinicopathological variables and survival outcomes. Functional preclinical studies were conducted in a panel of XRCC1 deficient and proficient Chinese hamster and Human cancer cells for cisplatin chemosensitivity. Clonogenic assay, neutral COMET assay, γH2AX immunocytochemistry and flow cytometric analyses were performed in cells. In ovarian cancer, 48% of the tumors were positive for XRCC1 expression and significantly associated with higher stage (p = 0.006), serous type tumors (p = 0.008), suboptimal de-bulking (p = 0.004) and platinum resistance (p < 0.0001). Positive XRCC1 had twofold increase of risk of death (p = 0.007) and progression (p < 0.0001). In the multivariate Cox model, XRCC1 expression was independently associated with cancer specific [p = 0.038] and progression free survival [p = 0.003]. Preclinically, XRCC1 negative cells were sensitive to cisplatin compared to XRCC1 positive cells. Sensitivity to cisplatin in XRCC1 negative cells was associated with accumulation of DNA double strand breaks and G2/M cell cycle arrest. XRCC1 expression is associated with adverse clinicopathological and survival outcomes in patients. Preclinical data provides mechanistic functional evidence for cisplatin sensitivity in XRCC1 negative cells. XRCC1 is a promising predictive biomarker in ovarian cancer.