Dataset Information

Overexpression of A613T and G462T variants of DNA polymerase ? weakens chemotherapy sensitivity in esophageal cancer cell lines.

ABSTRACT: BACKGROUND:Human DNA polymerase ? (pol?) is a small monomeric protein that is essential for short-patch base excision repair. It plays an important role in regulating the sensitivity of tumor cells to chemotherapy. METHODS:We evaluated the mutation of pol? in a larger cohort of esophageal cancer (EC) patients by RT-PCR and sequencing analysis. The function of the mutation was evaluated by CCK-8, in vivo tumor growth, and flow cytometry assays. RESULTS:There are 229 patients with the pol? mutation, 18 patients with A613T mutation, 12 patients with G462T mutation among 538 ECs. Analysis results of survival time showed that EC patients with A613T, G462T mutation had a shorter survival than the others (P < 0.05). CCK-8 and flow cytometry assays results showed the A613T, G462T EC9706 cells were less sensitive than WT cells to 5-FU and cisplatin (P < 0.05). Experiments results in vivo showed that the tumor sizes of A613T and G462T group were larger than WT and pol?-/- groups (P < 0.05). CONCLUSIONS:In this study, we discovered A to T point mutation at nucleotide 613 (A613T) and G to T point mutation at nucleotide 462 (G462T) in the pol? gene through 538 EC patients cohort study. A613T and G462T variant of DNA polymerase ? weaken chemotherapy sensitivity of esophageal cancer.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5103481 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Overexpression of A613T and G462T variants of DNA polymerase β weakens chemotherapy sensitivity in esophageal cancer cell lines.

Wang Yuanyuan Y Chen Xiaonan X Sun Qianqian Q Zang Wenqiao W Li Min M Dong Ziming Z Zhao Guoqiang G

Cancer cell international 20161110

<h4>Background</h4>Human DNA polymerase β (polβ) is a small monomeric protein that is essential for short-patch base excision repair. It plays an important role in regulating the sensitivity of tumor cells to chemotherapy.<h4>Methods</h4>We evaluated the mutation of polβ in a larger cohort of esophageal cancer (EC) patients by RT-PCR and sequencing analysis. The function of the mutation was evaluated by CCK-8, in vivo tumor growth, and flow cytometry assays.<h4>Results</h4>There are 229 patients ...[more]

PMID: 27843412

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Project description:BackgroundAdjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS). Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment. The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC).MethodsThe analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay. Kaplan-Meier analyses and Cox proportional hazards models were used to evaluate their associations with disease free survival (DFS) and OS of these ESCC patients receiving PAC. Receiving operating characteristic curve analysis was used to evaluate the role of the risk genotypes in the DFS and OS.ResultsWe found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS]. These HRs increased as the number of risk genotypes increased in the combined analysis. The model combining the risk genotypes with clinical characteristics or the TNM stage system was better in predicting outcomes in ESCC patients with PAC.ConclusionSNPs of ERCC2/XPD and ERCC5/XPG may independently and jointly predict survival of ESCC patients treated with PAC in this study population. Further validation in other study populations is warranted.

Dataset Information

Overexpression of A613T and G462T variants of DNA polymerase ? weakens chemotherapy sensitivity in esophageal cancer cell lines.

Publications

Overexpression of A613T and G462T variants of DNA polymerase β weakens chemotherapy sensitivity in esophageal cancer cell lines.

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