非小细胞肺癌长春瑞滨加顺铂方案化疗敏感性与XPC基因多态性及单体型的关系

目的基因多态预测肿瘤化疗药物敏感性对肿瘤个体化治疗具有重要意义,本文旨在探讨DNA修复基因XPC多态性及单体型对非小细胞肺癌（NSCLC）长春瑞滨加顺铂（NP）方案化疗敏感性的影响。方法 采用聚合酶链反应-限制性片段长度多态性技术检测163例NSCLC患者DNA修复基因XPC多态性及单体型;选择NP方案化疗,化疗2个周期后评价疗效,并分析化疗敏感性与XPC基因多态性的关系。结果与XPC Val499A la多态C/C基因型者相比,C/T＋T/T基因型的NSCLC患者化疗敏感性增大到2.166倍（P=0.048,OR=1.008-4.655）;与携带XPC PAT多态L等位基因者相比,携带S等位基因的个体化疗敏感性增大到2.353倍（P=0.034,OR=1.047-5.291）;以其他单体型者为参照,携带XPC C-L-A（Val499A la-PAT-Lys939G ln）单体型的个体在化疗无效组的比率（6.7%）显著高于有效组（0.0%）,差异有显著性（P=0.007）。结论携带XPC C-L-A（Val499A la、PAT、Lys939G ln）单体型患者对NP方案化疗应答差,XPC基因位点多态性对NSCLCNP方案化疗敏感性具有较好的预测作用。     

DNA修复基因XPD XPC XRCC4基因多态性与结直肠癌易感性的关联性研究

  目的  探讨DNA修复基因XPD rs13181（codon751A/C，Lys751Gln）、rs238406（codon156C/A，Arg156Arg）、XPC rs2279017（i11C/A）和XRCC4 rs3734091（codon247T/C，Ala247Ser）的单核苷酸多态性与结直肠癌易感性的关系。  方法  采用TaqMan技术对2013年4月至2016年1月北京肿瘤医院收治的338例结直肠癌患者（病例组）和315例健康者（对照组）进行多态位点基因型的检测。  结果  XPD rs13181基因型GT和等位基因G增加个体结直肠癌的发病风险（GT>TT，adjusted OR=1.69，95%CI:1.15~2.47，P=0.007；G>T，adjusted OR=1.77，95%CI:1.19~2.64，P=0.005）；XRCC4 rs3734091基因型GT和等位基因T增加个体结直肠癌的易感性（GT>GG，adjusted OR=9.02，95%CI:5.61~14.50，P＜0.001；T>G，adjusted OR=4.06，95%CI:2.49~6.61，P＜0.001）；XPD rs13181和rs238406的单倍体型GT显著降低结直肠癌的发病风险（adjusted OR=0.39，95%CI:0.18~0.85，P=0.018）。XPCrs2279017等位基因G和XRCC4 rs3734091等位基因T的联合效应（adjusted OR=28.43，95%CI:6.85~117.95，P＜0.001）以及XPD rs13181等位基因G和XRCC4 rs3734091等位基因T的联合效应（adjusted OR=10.24，95%CI:4.69~22.35，P＜0.001）显著增加个体结直肠癌的易感性。  结论  XPD rs13181和XRCC4 rs3734091位点的多态性与结直肠癌的易感性相关。      

The polyAT, intronic IVS11-6 and Lys939Gln XPC polymorphisms are not associated with transitional cell carcinoma of the bladder

Chemical carcinogens from cigarette smoking and occupational exposure are risk factors for bladder transitional cell carcinoma (TCC). The Xeroderma Pigmentosum Group C (XPC) gene is essential for repair of bulky adducts from carcinogens. The Xeroderma Pigmentosum Group C gene polymorphisms may alter DNA repair capacity (DRC), thus giving rise to genetic predisposition to bladder cancer. Recent studies have demonstrated linkage disequilibrium between three polymorphisms in the XPC gene (polyAT, IVS11-6 and Lys939Gln) and these have been shown to influence the DRC, as well as to be associated with bladder cancer risk. We analysed all three XPC polymorphisms in 547 bladder TCC patients and 579 cancer-free controls to investigate the association between these polymorphisms and bladder cancer susceptibility, and we also attempted to assess gene-environmental interactions. We confirmed strong linkage disequilibrium among the polymorphisms (Lewontin's D' > 0.99). Using logistic regression adjusting for smoking, occupational and family history, neither the heterozygote nor the homozygote variants of these polymorphisms were associated with increased bladder cancer risk (adjusted odds ratio [95% confidence interval] for heterozygote 0.82 [0.63-1.07], 0.82 [0.63-1.08] and 0.83 [0.63-1.08] for PolyAT, IVS11-6 and Lys939Gln, respectively and homozygote variant, 0.98 [0.68-1.42], 0.99 [0.69-1.43] and 1.01 [0.70-1.46]). Moreover, we did not find any significant interaction between these XPC polymorphisms and environmental exposure to cigarette smoking and occupational carcinogens.     

DNA修复基因XPC poly(AT)多态与食管癌遗传易感性的研究

目的探讨DNA修复基因XPC-PAT多态与食管癌遗传易感性的关系。方法采用病例-对照分子流行病学方法,分析了182例食管癌患者和375例正常对照的XPC-PAT基因型分布,比较不同基因型与食管癌风险的关系。结果多因素回归分析表明,与LS和SS基因型比较,LL基因型与食管癌风险增高相关(校正OR 1．43;95%CI 1．01-2．02)。性别分析表明,LL基因型与食管癌风险的关系主要表现在男性(校正OR 1．54,95%CI 1．02-2．32)。年龄分析表明,LL基因型增加食管癌风险主要见于＞55岁的人群(校正OR 2．10,95% CI 1．27-3．47)。该基因多态与吸烟状态及吸烟量无联合作用。结论DNA修复基因XPC-PAT多态与食管癌风险相关。     

XPC、XPG基因单核苷酸多态性与肿瘤遗传易感性关系的研究进展

肿瘤的发生是多基因参与、多因素作用的复杂过程,是基因-基因、基因-环境的交互作用导致的结果。XPC、XPG基因是DNA损伤修复系统中核苷酸切除修复途径的核心基因,这2个基因存在单核苷酸多态性,影响个体患肿瘤的遗传易感性,并与相关环境暴露因素存在交互作用,影响肿瘤的患病风险。XPC、XPG基因单核苷酸多态性的研究结果对评价遗传与环境因素对肿瘤的危险性、阐明肿瘤发生的分子遗传学机制、明确肿瘤高危个体以及肿瘤早期诊断和治疗等有重要意义。     

DNA修复基因XPC研究进展

体内存在多种修复DNA损伤的机制,核苷酸切除修复（NER）是最重要的DNA损伤修复系统,着色性干皮病基因组C（XPC）是NER系统的重要成分,它与HHR23B形成复合物,参与DNA损伤识别和NER的启动,其基因突变可引起整个核苷酸切除通路的缺陷和着色性干皮病表型。因此对XPC的生物学特性及功能与NER、肿瘤之间关系的研究具有重要的意义。     

Associations of Lys939Gln and Ala499Val polymorphisms of the XPC gene with cancer susceptibility: A meta‐analysis

XPC polymorphisms may alter DNA repair capacity, thus leading to genetic instability and carcinogenesis. Numerous studies have investigated the associations of XPC Lys939Gln (rs2228001) and Ala499Val (rs2228000) polymorphisms with cancer susceptibility; however, the findings are inconclusive. We searched literature from MEDLINE and EMBASE for eligible publications that assessed the associations between these two polymorphisms and cancer risk. We also assessed genotype‐mRNA expression correlation data from HapMap for rs2228001 and rs2228000 in normal cell lines derived from 270 subjects with different ethnicities. The final analysis included 62 published studies of 25,708 cases and 30,432 controls for the Lys939Gln and 34 studies with 14,877 cases and 17,888 controls for the Ala499Val. Overall, Lys939Gln was significantly associated with an increased overall cancer risk (Gln/Gln vs. Lys/Lys: OR = 1.16, 95% CI = 1.07 − 1.25, p < 0.001; recessive model: OR = 1.14, 95% CI = 1.06 − 1.22, p < 0.001; dominant model: OR = 1.06, 95% CI = 1.01 − 1.11, p = 0.015 and Gln vs. Lys: OR = 1.07, 95% CI = 1.03 − 1.10, p < 0.001) and further stratifications showed an increased risk for bladder, lung and colorectal cancer, Asian populations and population‐based studies. Likewise, Ala499Val was also significantly associated with an increased overall cancer risk (Val/Val vs. Ala/Ala: OR = 1.21, 95% CI = 1.07 − 1.36, p = 0.003 and recessive model: OR = 1.20, 95% CI = 1.08 − 1.34, p = 0.001) and further stratification showed an increased risk for breast and bladder cancer, particularly in Asian populations. Interestingly, significantly correlation between XPC genotypes and mRNA expression was found only for Asian populations as well. Despite some limitations, this meta‐analysis established some solid statistical evidence for an association between XPC polymorphisms and cancer risk, which warrants further validation in single large studies.     

DNA repair as an emerging target for COPD-lung cancer overlap

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD). Many of the detrimental effects of cigarette smoke have been attributed to the development of DNA damage, either directly from chemicals contained in cigarette smoke or as a product of cigarette smoke-induced inflammation and oxidative stress. In this review, we discuss the environmental, epidemiological, and physiological links between COPD and lung cancer and the likely role of DNA damage and repair in COPD and lung cancer development. We explore alterations in DNA damage repair by DNA repair proteins and pathways. We discuss emerging data supporting a key role for the DNA repair protein, xeroderma pigmentosum group C (XPC), in cigarette smoke-induced COPD and early lung cancer development. Understanding the interplay between cigarette smoke, DNA damage repair, COPD, and lung cancer may lead to prognostic tools and new, potentially targetable, pathways for lung cancer prevention and treatment.