title: 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.
authors.affiliation: Department of Clinical Oncology, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Tarek
authors.initials: T
authors.lastname: Abdel-Fatah
authors.forename: Rebeka
authors.initials: R
authors.lastname: Sultana
authors.forename: Rachel
authors.initials: R
authors.lastname: Abbotts
authors.forename: Claire
authors.initials: C
authors.lastname: Hawkes
authors.forename: Claire
authors.initials: C
authors.lastname: Seedhouse
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D010984:Platinum / Q000627:therapeutic use; D034622:RNA Interference; D016896:Treatment Outcome; D014410:Tumor Stem Cell Assay; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D010984:Platinum