Graziano Francesco, Kawakami Kazuyuki, Watanabe Go, Ruzzo Annamaria, Humar Bostjan, Santini Daniele, Catalano Vincenzo, Ficarelli Rita, Merriman Tony, Panunzi Simona, Testa Enrica, Cascinu Stefano, Bearzi Italo, Tonini Giuseppe, Magnani Mauro
Medical Oncology, Hospital of Urbino, Italy.
Int J Cancer. 2004 Dec 20;112(6):1010-4. doi: 10.1002/ijc.20489.
We investigated in a case-control study a possible role of thymidylate synthase gene (TS) polymorphisms for gastric cancer susceptibility. Lymphocyte genomic DNA from 134 Italian gastric cancer patients and 139 controls was used for genotyping two polymorphisms in the TS 5'-untranslated region (5'-UTR); a double (2R) or triple (3R) 28-bp repeat and a G/C polymorphism within the triple repeats allele (3G allele). Samples were also genotyped at a 6-bp deletion/insertion (del6 or ins6) polymorphism at position 1494 in the TS 3'-untranslated region (3'-UTR). Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with the disease. The global allelic distribution was in Hardy-Weinberg equilibrium. Genotypes with the 3G allele (2R/3G, 3C/3G, 3G/3G) were significantly more frequent in patients than controls and were associated with gastric cancer risk (OR = 2.06; 95% CI = 1.26-3.35). A significant risk was also observed for carriers of the del6 allele in the 3'-UTR. Odds ratios for combined 3G-del6/ins6 and 3G-del6/del6 genotypes were 2.59 (95% CI = 1.36-4.94) and 2.81 (95% CI = 1.22-6.64), respectively. The 3G-del6 haplotype showed a significant association with the disease (p = 0.01). Polymorphisms in the TS gene may contribute to gastric cancer susceptibility and this finding deserve further investigation in the context of novel strategies for gastric cancer prevention. In vitro, 3G genotypes have been related to high TS mRNA expression, which may underlie one of the possible etiologic mechanisms.
我们在一项病例对照研究中，调查了胸苷酸合成酶基因（TS）多态性在胃癌易感性中可能发挥的作用。利用134名意大利胃癌患者和139名对照者的淋巴细胞基因组DNA，对TS 5'非翻译区（5'-UTR）中的两个多态性进行基因分型；一个28bp的双重复（2R）或三重复（3R），以及三重复等位基因（3G等位基因）内的一个G/C多态性。还对TS 3'非翻译区（3'-UTR）第1494位的一个6bp缺失/插入（del6或ins6）多态性进行基因分型。采用比值比（OR）和95%置信区间（CI）的无条件回归、单倍型和连锁不平衡分析，研究这些多态性与疾病的关联。总体等位基因分布符合哈迪-温伯格平衡。携带3G等位基因的基因型（2R/3G、3C/3G、3G/3G）在患者中显著多于对照者，并与胃癌风险相关（OR = 2.06；95%CI = 1.26 - 3.35）。在3'-UTR中，del6等位基因携带者也观察到显著风险。3G-del6/ins6和3G-del6/del6组合基因型的比值比分别为2.59（95%CI = 1.36 - 4.94）和2.81（95%CI = 1.22 - 6.64）。3G-del6单倍型与疾病显示出显著关联（p = 0.01）。TS基因多态性可能与胃癌易感性有关，这一发现值得在胃癌预防新策略的背景下进一步研究。在体外，3G基因型与TS mRNA高表达有关，这可能是一种可能的病因机制之一。
