Hashibe Mia, Boffetta Paolo, Zaridze David, Shangina Oxana, Szeszenia-Dabrowska Neonila, Mates Dana, Janout Vladimir, Fabiánová Eleonóra, Bencko Vladimir, Moullan Norman, Chabrier Amelie, Hung Rayjean, Hall Janet, Canzian Federico, Brennan Paul
IARC, Lyons, France.
Cancer Epidemiol Biomarkers Prev. 2006 Apr;15(4):696-703. doi: 10.1158/1055-9965.EPI-05-0710.
Incidence and mortality rates of upper aerodigestive tract cancers in Central Europe are among the highest in the world and have increased substantially in recent years. This increase is likely to be due to patterns of alcohol and tobacco consumption. Genetic susceptibility to upper aerodigestive tract cancer in relation to such exposures is an important aspect that should be investigated among populations in this region.
A multicenter case-control study comprising 811 upper aerodigestive tract cancer cases and 1,083 controls was conducted in: Bucharest (Romania), Lodz (Poland), Moscow (Russia), Banska Bystrika (Slovakia), and Olomouc and Prague (Czech Republic). We analyzed six SNPs in three genes related to ethanol metabolism: alcohol dehydrogenase 1B and 1C (ADH1B, ADH1C) and aldehyde dehydrogenase 2 (ALDH2).
The ADH1B histidine allele at codon 48 was associated with a decreased risk of upper aerodigestive tract cancer; odds ratios (OR) were 0.36 [95% confidence interval (95% CI), 0.17-0.77] for medium/heavy drinkers and 0.57 (95% CI, 0.36-0.91) for never/light drinkers. Moderately increased risks were observed for the ADH1C (350)Val allele (OR, 1.19; 95% CI, 0.98-1.55) and ADH1C (272)Gln allele (OR, 1.24; 95% CI, 0.98-1.55). Medium/heavy drinkers who were heterozygous or homozygous at ALDH2 nucleotide position 248 were at a significantly increased risk of upper aerodigestive tract cancer (OR, 1.76; 95% CI, 1.13-2.75; OR, 5.79; 95% CI, 1.49-22.5, respectively), with a significant dose response for carrying variant alleles (P = 0.0007). Similar results were observed for the ALDH2 +82A>G and ALDH2 -261C>T polymorphisms. When results were analyzed by subsite, strong main effects were observed for squamous cell carcinoma of the esophagus for all six variants. Among the 30% of the population who were carriers of at least one ALDH2 variant, the attributable fraction among carriers (AF(c)) was 24.2% (5.7-38.3%) for all upper aerodigestive tract cancers, increasing to 58.7% (41.2-71.0%) for esophageal cancer. Among carriers who drank alcohol at least thrice to four times a week, the AF(c) for having at least one ALDH2 variant was 49% (21.3-66.8%) for all upper aerodigestive tract cancers, increasing to 68.9% (42.9-83.1%) for esophageal cancer.
Polymorphisms in the ADH1B and ALDH2 genes are associated with upper aerodigestive tract cancer in Central European populations and interact substantially with alcohol consumption.
中欧上呼吸消化道癌症的发病率和死亡率位居世界前列，且近年来大幅上升。这种增长可能归因于酒精和烟草的消费模式。上呼吸消化道癌症的遗传易感性与这些暴露因素的关系是该地区人群中应加以研究的一个重要方面。
在布加勒斯特（罗马尼亚）、罗兹（波兰）、莫斯科（俄罗斯）、班斯卡-比斯特里察（斯洛伐克）以及奥洛穆茨和布拉格（捷克共和国）开展了一项多中心病例对照研究，共纳入811例上呼吸消化道癌症病例和1083例对照。我们分析了与乙醇代谢相关的三个基因中的六个单核苷酸多态性（SNP）：乙醇脱氢酶1B和1C（ADH1B、ADH1C）以及乙醛脱氢酶2（ALDH2）。
密码子48处的ADH1B组氨酸等位基因与上呼吸消化道癌症风险降低相关；中/重度饮酒者的优势比（OR）为0.36 [95%置信区间（95%CI），0.17 - 0.77]，从不饮酒/轻度饮酒者的OR为0.57（95%CI，0.36 - 0.91）。观察到ADH1C（350）缬氨酸等位基因（OR，1.19；95%CI，0.98 - 1.55）和ADH1C（272）谷氨酰胺等位基因（OR，1.24；95%CI，0.98 - 1.55）的风险适度增加。ALDH2核苷酸位置248处杂合或纯合的中/重度饮酒者患 上呼吸消化道癌症的风险显著增加（OR分别为1.76；95%CI，1.13 - 2.75；OR为5.79；95%CI，1.49 - 22.5），携带变异等位基因存在显著的剂量反应关系（P = 0.0007）。对于ALDH2 +82A>G和ALDH2 -261C>T多态性也观察到类似结果。按亚部位分析结果时，所有六个变异对上消化道鳞状细胞癌均观察到强烈的主要效应。在至少携带一种ALDH2变异的30%人群中，所有上呼吸消化道癌症携带者中的归因分数（AF(c)）为24.2%（5.7 - 38.3%），食管癌则增至58.7%（41.2 - 71.0%）。在每周至少饮酒三至四次的携带者中，至少携带一种ALDH2变异的所有上呼吸消化道癌症的AF(c)为49%（21.3 - 66.8%），食管癌则增至68.9%（42.9 - 83.1%）。
ADH1B和ALDH2基因的多态性与中欧人群的上呼吸消化道癌症相关，且与酒精消费存在显著相互作用。
