Clinicopathological and functional significance of XRCC1 expression in ovarian cancer

• Published in: International journal of cancer Vol. 132; no. 12; pp. 2778 - 2786
• Main Authors: Abdel‐Fatah, Tarek, Sultana, Rebeka, Abbotts, Rachel, Hawkes, Claire, Seedhouse, Claire, Chan, Stephen, Madhusudan, Srinivasan
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.06.2013; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cancer; Cell cycle; Cell Line; Chemotherapy; Cricetinae; Disease Progression; DNA repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug resistance; Female; Gene Expression; Gene Silencing; Humans; Medical research; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Platinum - therapeutic use; platinum therapy; predictive; prognostic biomarker; RNA Interference; Treatment Outcome; Tumor Stem Cell Assay; Tumors; X-ray Repair Cross Complementing Protein 1; XRCC1; Antineoplastic agent; Human; platinum therapy; Prognosis; ovarian cancer; Ovary cancer; Biological marker; predictive; XRCC1; Malignant tumor; Gene expression; DNA repair; Cisplatin; Female genital diseases; Repair gene; Ovarian diseases; Alkylating agent; Cancerology; Treatment; Chemosensitivity; Genetics; prognostic biomarker; Cancer; Platinum II Complexes
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27980

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. What's new? Resistance to platinum chemotherapy negatively impacts patient outcomes in ovarian cancer, and proficient DNA repair is an important mechanism underlying such resistance. With XRCC1 being a key player in DNA repair, here the authors set to investigate its expression in ovarian cancer. They show for the first time that XRCC1 expression is associated with adverse clinicopathological features in ovarian cancer and also predicts platinum resistance and poor survival outcomes. Using preclinical models, the authors also demonstrate that XRCC1 deficiency results in sensitivity to cisplatin and provide mechanistic confirmation that XRCC1 is a promising predictive biomarker in ovarian cancer.