Genetic Associations of 115 Polymorphisms with Cancers of the Upper Aerodigestive Tract across 10 European Countries: The ARCAGE Project
Genetic Associations of 115 Polymorphisms with Cancers of the Upper Aerodigestive Tract across 10 European Countries: The ARCAGE Project
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DOI：
10.1158/0008-5472.can-08-2604
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Brennan, Paul
中科院分区：
文献类型：
--
作者：
Canova, Cristina;Hashibe, Mia;Brennan, Paul
上呼吸消化道（UADT）癌症包括口腔、咽、喉和食管的恶性肿瘤，占欧洲所有新发癌症的6.4%。在10个欧洲国家的14个中心进行的一项多中心病例对照研究（ARCAGE研究）中，研究了来自62个优先选择基因的115个单核苷酸多态性（SNP）与UADT癌症的关系。我们发现了11个与UADT癌症总体统计学相关的SNP（预期5.75）。考虑到假阳性结果的可能性，我们重点关注CYP 2A 6、MDM 2、肿瘤坏死因子（TNF）和鳞状细胞癌1（GASC 1）扩增基因中的SNP，在UADT癌症总体或亚位点的主效应分析中观察到趋势的低P值（P趋势<0. 01）。CYP 2A 6 - 47 A>C（rs 28399433）是一种1期代谢基因，其罕见变异与UADT癌症风险降低相关（P趋势= 0.01）。MDM 2基因中涉及细胞周期控制的三个SNP与UADT癌症相关。MDM 2 IVS 5 + 1285 A>G（rs3730536）表现出较强的共显性效应（P趋势= 0.007）。TNF基因中两个SNP的罕见变异与风险降低相关;对于TNF IVS 1 + 123 G>A（rs 1800610），P趋势为0.007。发现GASC 1的两个SNPs的变体与UADT癌症风险增加密切相关（对于两者，P趋势= 0.008）。这项研究是欧洲最大的UADT癌症遗传流行病学研究。我们的分析指出了各种途径中的潜在相关基因。[Cancer Res 2009;69（7）：2956-65]
Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend < 0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase 1 metabolism gene, was associated with reduced UADT cancer risk (P trend = 0.01). Three SNPs in the,MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend = 0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend = 0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways. [Cancer Res 2009;69(7):2956-65]