Ulybina Yulia M, Kuligina Ekatherina Sh, Mitiushkina Nathalia V, Rozanov Maxim E, Ivantsov Alexandr O, Ponomariova Daria N, Togo Alexandr V, Levchenko Evgeny V, Shutkin Vladimir A, Brenister Sergiu I, Devilee Peter, Zhivotovsky Boris, Hirvonen Ari, Imyanitov Evgeny N
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Moldovian Institute of Oncology, Kishinev 2025, Republic of Moldova.
Cancer Lett. 2009 Jun 18;278(2):183-191. doi: 10.1016/j.canlet.2009.01.012. Epub 2009 Feb 8.
Apoptosis plays a role in the elimination of DNA-damaged cells thus protecting the host from cancer development. Some data indicate that normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. We tested 19 coding apoptotic gene SNPs in 2-stage molecular epidemiological study. For the preliminary sorting of SNP candidates, we employed a "comparison of extremes" approach, where 111 patients with highly pronounced LC susceptibility (non-smokers or young-onset light smokers) were analyzed against 110 subjects with the evidence for LC tolerance (elderly tumor-free heavy smokers). Three genotypes demonstrated possible association with LC risk (Leu/Leu-homozygotes for Casp5 Val318Leu versus other genotypes: OR=2.47 (95% CI: 1.07-5.69), p=0.03; His-carriers for Casp8 His302Asp: OR=2.26 (95% CI: 1.18-4.31), p=0.02; Arg-carriers for DR4 Lys441Arg: OR=1.89 (95% CI: 1.05-3.40), p=0.03), and therefore were selected for the validation. The extended study included 2 case-control series, namely subjects from Russia (351 LC cases and 538 controls) and Moldova (296 LC cases and 295 controls). Interestingly, all three candidate genotypes consistently demonstrated OR above 1 both in Russian and in Moldovian groups. Although the combined Mantel-Haenszel analysis yet failed to reach statistical significance (OR=1.22 (95% CI: 0.90-1.65), p=0.21; OR=1.17 (95% CI: 0.92-1.50), p=0.21; OR=1.19 (95% CI: 0.95-1.51), p=0.14, respectively), the obtained data indicate that Casp5, Casp8 and DR4 gene polymorphisms may deserve consideration in large-scale case-control studies of LC risk modifiers.
细胞凋亡在清除DNA损伤细胞中发挥作用，从而保护宿主免受癌症发展的影响。一些数据表明，凋亡基因序列中的正常变异可能导致凋亡能力欠佳，进而增加患癌风险。我们在一项两阶段分子流行病学研究中检测了19个编码凋亡基因的单核苷酸多态性（SNP）。为了对SNP候选基因进行初步筛选，我们采用了一种“极端比较”方法，即对111例LC易感性极高的患者（不吸烟者或年轻起病的轻度吸烟者）与110例有LC耐受性证据的受试者（无肿瘤的老年重度吸烟者）进行分析。三种基因型显示出与LC风险可能存在关联（Casp5 Val318Leu的Leu/Leu纯合子与其他基因型相比：OR = 2.47（95%CI：1.07 - 5.69），p = 0.03；Casp8 His302Asp的His携带者：OR = 2.26（95%CI：1.18 - 4.31），p = 0.02；DR4 Lys441Arg的Arg携带者：OR = 1.89（95%CI：1.05 - 3.40），p = 0.03），因此被选来进行验证。扩展研究包括2个病例对照系列，即来自俄罗斯的受试者（351例LC病例和538例对照）和摩尔多瓦的受试者（296例LC病例和295例对照）。有趣的是，在俄罗斯和摩尔多瓦组中，所有三种候选基因型的OR值始终高于1。尽管合并的Mantel - Haenszel分析尚未达到统计学显著性（OR分别为1.22（95%CI：0.90 - 1.65），p = 0.21；OR = 1.17（95%CI：0.92 - 1.50），p = 0.21；OR = 1.19（95%CI：0.95 - 1.51），p = 0.14），但所获得的数据表明，在大规模的LC风险修饰因子病例对照研究中，Casp5、Casp8和DR4基因多态性可能值得考虑。
