title: Clinical significance of a point mutation in DNA polymerase beta (POLB) gene in gastric cancer.
abstract: Gastric cancer (GC) is a major cause of global cancer mortality. Genetic variations in DNA repair genes can modulate DNA repair capability and, consequently, have been associated with risk of developing cancer. We have previously identified a T to C point mutation at nucleotide 889 (T889C) in DNA polymerase beta (POLB) gene, a key enzyme involved in base excision repair in primary GCs. The purpose of this study was to evaluate the mutation and expression of POLB in a larger cohort and to identify possible prognostic roles of the POLB alterations in GC. Primary GC specimens and their matched normal adjacent tissues were collected at the time of surgery. DNA, RNA and protein samples were isolated from GC specimens and cell lines. Mutations were detected by PCR-RFLP/DHPLC and sequencing analysis. POLB gene expression was examined by RT-PCR, tissue microarray, Western blotting and immunofluorescence assays. The function of the mutation was evaluated by chemosensitivity, MTT, Transwell matrigel invasion and host cell reactivation assays. The T889C mutation was detected in 18 (10.17%) of 177 GC patients. And the T889C mutation was associated with POLB overexpression, lymph nodes metastases and poor tumor differentiation. In addition, patients with- the mutation had significantly shorter survival time than those without-, following postoperative chemotherapy. Furthermore, cell lines with T889C mutation in POLB gene were more resistant to the treatment of 5-fluorouracil, cisplatin and epirubicin than those with wild type POLB. Forced expression of POLB gene with T889C mutation resulted in enhanced cell proliferation, invasion and resistance to anticancer drugs, along with increased DNA repair capability. These results suggest that POLB gene with T889C mutation in surgically resected primary gastric tissues may be clinically useful for predicting responsiveness to chemotherapy in patients with GC. The POLB gene alteration may serve as a prognostic biomarker for GC.
authors.affiliation: 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education); ; 4. Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Tan
authors.affiliation: 2. Department of Sugary, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, 100142, P.R. China.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Wang
authors.affiliation: 3. Department of Genetics, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.affiliation: 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education);
authors.forename: Shuyang
authors.initials: S
authors.lastname: Ren
authors.affiliation: 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education);
authors.forename: Wenmei
authors.initials: W
authors.lastname: Li
authors.affiliation: 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education);
authors.forename: Jiantao
authors.initials: J
authors.lastname: Cui
authors.affiliation: 4. Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Harindarpal S
authors.initials: HS
authors.lastname: Gill
authors.affiliation: 4. Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Sidney W
authors.initials: SW
authors.lastname: Fu
authors.affiliation: 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education);
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019951:DNA Polymerase beta / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019951:DNA Polymerase beta
keywords: DNA Repair; DNA polymerase beta (POLB); chemotherapy.; gastric cancer; point mutation