Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran.
Candidate gene association study of esophageal squamous cell carcinoma in a high-risk region in Iran.
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DOI：
10.1158/0008-5472.can-09-1149
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Narod SA
中科院分区：
文献类型：
--
作者：
Akbari MR;Malekzadeh R;Shakeri R;Nasrollahzadeh D;Foumani M;Sun Y;Pourshams A;Sadjadi A;Jafari E;Sotoudeh M;Kamangar F;Boffetta P;Dawsey SM;Ghadirian P;Narod SA
伊朗东北部的一个食道鳞状细胞癌(ESCC)高危地区在30多年前被发现。此前的研究表明，遗传因素在该地区癌症高发中发挥了作用。在不同的人群中，一些基因的多态与食道癌的易感性有关，但在伊朗还没有对这些基因进行研究。我们从15个以前被认为与ESCC风险增加相关的基因中选择了22个功能变异(和130个相关的tag SNPs)。我们对来自451名土库曼斯坦人(197名病例和254名对照)的初级样本进行了基因分型。152个变异中有7个与ESCC相关，P=0.05；然后在显性和隐性模式下对1668例病例和对照(土库曼斯坦人和非土库曼人)进行了这些SNP的验证研究。在联合样本集中，来自5个不同基因的5个变异与ESCC在P=0.05水平上显示出显著的相关性。例如，在ADH1B中，这种关联很强，在土库曼人和非土库曼人中都存在。在隐性遗传模式下，ADH1B基因第48位组氨酸等位基因与食管鳞癌发病风险显著相关(OR=0.41，95%，CI=0.19~0.49；P=4×10−4)。对于另外四个变异，土库曼斯坦亚组中存在关联，但这些变异的统计意义没有ADH1B那么令人信服。两个变种显示了有害的影响，两个是保护性的。CCND1C.870A和GT；G等位基因与隐性模式下食管鳞癌发病风险增加1.5倍(OR=1.5 0，95%CI=1.14~2.16，P=0.02)，rs1625895基因A等位基因与显性模式下食管鳞癌发病风险增加1.5倍(OR=1.54，95%CI=1.21~4.07，P=0.005)。在隐性模式下，ALDH2基因rs886205变异的C等位基因与食管鳞癌的风险降低相关(OR=0.58，95%CI=0.34~0.87，P=0.02)，Rs7087131变异的A等位基因与隐性模式下食管鳞癌的风险降低相关(OR=0.26，95%CI=0.05~0.49，P=0.01)。这些结果证实了ESCC的遗传易感性在居住在伊朗东北部的土库曼斯坦人中这种癌症的高发病率中起到了作用。
A region with a high risk for esophageal squamous cell carcinoma (ESCC) in northeast of Iran was identified more than three decades ago. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. Polymorphisms of several genes have been associated with susceptibility to esophageal cancer in various populations, but these have not been studied in Iran. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes which previously have been suggested to be associated with an increased risk of ESCC. We genotyped a primary set of samples from 451 Turkmen (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these SNPs were then studied in a validation set of 1668 cases and controls (Turkmen and non-Turkmen) under dominant and recessive models. In the joint sample set, five variants, from five different genes, showed significant associations with ESCC at the P = 0.05 level. For one variant, in ADH1B, the association was strong and was present in both Turkmen and non-Turkmen. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC under a recessive model (OR = 0.41, 95%, CI = 0.19 to 0.49; P = 4×10−4). For four additional variants, an association was present in the Turkmen subgroup, but the statistical significance of these was less compelling than for ADH1B. Two variants showed deleterious effects and two were protective. The G allele of the c.870A>G variant of CCND1 gene was associated with a 1.5-fold increased risk of ESCC under the recessive model (OR = 1.50, 95% CI = 1.14 to 2.16, P = 0.02) and the A allele of the rs1625895 variant of TP53 gene was associated with a 1.5-fold increased risk of ESCC under a dominant model (OR = 1.54, 95% CI = 1.21 to 4.07, P = 0.005). The C allele of the rs886205 variant of ALDH2 was associated with a decreased risk of ESCC under a recessive model (OR = 0.58, 95% CI = 0.34 to 0.87, P = 0.02) and the A allele of the rs7087131 variant of MGMT was associated with a decreased risk of ESCC under the recessive model (OR = 0.26, 95% CI = 0.05 to 0.49, P=0.01). These results confirm that genetic predisposition to ESCC plays a role in high incidence of this cancer among Turkmens who live in northeast of Iran.