Clinical significance of a point mutation in DNA polymerase beta (POLB) gene in gastric cancer.
Clinical significance of a point mutation in DNA polymerase beta (POLB) gene in gastric cancer.
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DOI：
10.7150/ijbs.10692
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发表时间：
2015
影响因子：
9.2
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Tan X;Wang H;Luo G;Ren S;Li W;Cui J;Gill HS;Fu SW;Lu Y
胃癌（GC）是全球癌症死亡率的主要原因。DNA修复基因的遗传变异可以调节DNA修复能力，因此与患癌症的风险有关。我们以前已经确定了在DNA聚合酶β（POLB）基因，一个关键酶参与在原发性GC的碱基切除修复的核苷酸889（T889 C）的T到C点突变。本研究的目的是在更大的队列中评估POLB的突变和表达，并确定POLB改变在GC中可能的预后作用。在手术时收集原发性GC标本及其匹配的正常邻近组织。从GC标本和细胞系中分离DNA、RNA和蛋白质样品。采用PCR-RFLP/DHPLC和测序分析检测突变。采用RT-PCR、组织芯片、Western blotting和免疫荧光检测POLB基因表达。通过化疗敏感性、MTT、Transwell Matrigel侵袭和宿主细胞再活化试验评估突变的功能。177例胃癌患者中18例（10.17%）存在T889 C突变。T889 C突变与POLB过度表达、淋巴结转移和肿瘤分化差有关。此外，术后化疗后，携带-突变的患者的生存时间明显短于不携带-突变的患者。此外，POLB基因T889 C突变的细胞系对5-氟尿嘧啶、顺铂和表阿霉素的耐药性高于野生型POLB。T889 C突变的POLB基因的强制表达导致细胞增殖、侵袭和抗癌药物抗性增强，并沿着DNA修复能力的增强。这些结果表明，POLB基因T889 C突变的手术切除的原发性胃组织中可能是临床上有用的预测胃癌患者对化疗的反应。POLB基因改变可作为胃癌预后的生物标志物。
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.
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