Xeroderma pigmentosum complementation group C single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer
Xeroderma pigmentosum complementation group C single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer
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DOI：
10.1002/cncr.26329
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发表时间：
2012-02-01
期刊：
影响因子：
6.2
通讯作者：
Walsh, Christine S.
中科院分区：
文献类型：
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作者：
Fleming, Nicole D.;Agadjanian, Hasmik;Walsh, Christine S.
背景：核苷酸切除修复（NER）途径是去除大体积铂DNA加合物的主要DNA修复途径。次优DNA修复可能导致对铂剂的反应改善。本研究的目的是确定NER通路基因的单核苷酸多态性（SNPs）是否可以作为卵巢癌铂类药物反应的标志物。方法：作者确定了晚期乳头状浆液性卵巢癌患者，他们接受了原发性细胞减灭术，随后接受了以铂为基础的化疗。从外周血标本中分离DNA。使用聚合酶链反应分析对NER基因内的22个SNP（着色性干皮病[XP]互补组A [XPA]、XPB/切除修复交叉互补啮齿动物修复缺陷，互补组3 [ERCC 3]、XPC、XPD/ERCC 2、XPF/ERCC 4、XPG/ERCC 5、科凯恩综合征组B蛋白[CS B]/ERCC 8、ERCC 1）进行基因分型。结果：共对139例III期和IV期乳头状浆液性卵巢癌患者进行了基因分型。XPC（参考SNP 3731108 [rs3731108]）腺苷-鸟嘌呤（AG）/AA基因型与GG基因型相比，与无进展生存期（PFS）延长相关，分别为21.3个月与13.4个月（风险比[HR]，0.63; 95%置信区间[CI]，0.42- 0.95; P.03）。与TT基因型相比，XPC（rs 1124303）鸟苷-胸苷（GT）/GG基因型与PFS延长相关，分别为22.8个月和14.9个月（HR，0.47; 95% CI，0.24- 0.94; P.03）。XPC聚（AT）（PAT）（-/+）/（-/+）基因型与（+/+）基因型相比，PFS延长17个月与11.6个月（HR，0.56; 95% CI，0.36- 0.89; P.01）。与TT基因型相比，XPF/ERCC 4（rs 12926685）胞苷-胸苷（CT）/CC基因型与PFS延长相关，分别为16.7个月和12.4个月（HR，0.63; 95% CI，0.41- 0.95; P.03）。在调整乳腺癌（BRCA）基因和细胞减灭术状态的多变量分析中，XPC SNP与PFS延长显著相关。结论：目前的研究结果表明，XPC是NER途径的一个关键组成部分，参与DNA损伤修复。XPC基因中的SNPs可能是卵巢癌对铂类化疗反应的新标志物。Cancer 2012; 118：689- 97. (C)2011年美国癌症协会
BACKGROUND: The nucleotide excision repair (NER) pathway is the principal DNA repair pathway for removing bulky platinum DNA adducts. Suboptimal DNA repair may lead to improved response to platinum agents. The objective of this study was to determine whether single-nucleotide polymorphisms (SNPs) in NER pathway genes could be markers of platinum response in ovarian cancer. METHODS: The authors identified patients with advanced- stage, papillary serous ovarian cancer who underwent primary cytoreductive surgery followed by platinum- based chemotherapy. DNA was isolated from peripheral blood specimens. Twenty- two SNPs within NER genes (xeroderma pigmentosum [XP] complementation group A [XPA], XPB/excision repair cross- complementing rodent repair deficiency, complementation group 3 [ERCC3], XPC, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5, Cockayne syndrome group B protein [CSB]/ERCC8, ERCC1) were genotyped using polymerase chain reaction analysis. RESULTS: In total, 139 patients with stage III and IV papillary serous ovarian cancer were genotyped. The XPC (reference SNP 3731108 [rs3731108]) adenosine- guanine (AG)/AA genotype versus the GG genotype was associated with prolonged a progression- free survival (PFS) of 21.3 months versus 13.4 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42- 0.95; P.03). The XPC (rs1124303) guanosine- thymidine (GT)/GG genotype versus the TT genotype was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR, 0.47; 95% CI, 0.24- 0.94; P.03). The XPC poly(AT) (PAT) (-/+)/(-/+) genotype versus the (+/+) genotype was associated with a prolonged PFS of 17 months versus 11.6 months (HR, 0.56; 95% CI, 0.36- 0.89; P.01). The XPF/ERCC4 (rs12926685) cytidine- thymidine (CT)/CC genotype versus the TT genotype was associated with a prolonged PFS of 16.7 months versus 12.4 months (HR, 0.63; 95% CI, 0.41- 0.95; P.03). On multivariate analysis adjusting for breast cancer (BRCA) gene and cytoreductive surgery status, the XPC SNPs remained significantly associated with prolonged PFS. CONCLUSIONS: The current results indicated that XPC is a key component of the NER pathway that participates in DNA damage repair. SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum- based chemotherapy. Cancer 2012; 118: 689- 97. (C) 2011 American Cancer Society.