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Gastroenterology:科学家发现四个结肠癌相关基因

来源:生物谷 2013-02-21 20:02

2013年2月21日讯 /生物谷BIOON/--由生物学家Peters博士和生物统计学家Hsu Li博士领导的多国科学家组成的国际研究团队近期发现了四个基因的多态性与结肠癌发病率增高有很强的相关性。相关文章将发表在四月份的Gastroenterology上。

Peters领导的研究团队四年来一直致力于研究结肠癌相关基因,该团队研究人员来自于北美,澳大利亚和欧洲。研究人员分析了近四万人的基因组,被试者的一半是结肠癌患者。

全基因组相关性分析研究包括了两个阶段。第一阶段包括快速分析12,696位患有结肠癌或癌前疾病的被试的DNA。接着研究人员将分析数据与15,113位健康欧洲人进行比对。在分析的27万个遗传多态性中,研究人员进一步在3056位结肠癌病人或者癌前疾病的被试和6658位健康欧洲、亚洲人中,分析了10个与结肠癌相关性最显著的突变。

研究人员发现了如下前人未报道与结肠癌相关的基因:NABP,DNA修复相关基因;LAMC1,第二个与结肠癌相关的层粘连蛋白基因家族基因;CCND2,参与控制细胞周期基因;TBX3,转录因子,其靶标之一是已知的结肠癌通路基因。如果携带一个或两个如上基因拷贝,结肠癌发病率会增加10%-40%。(生物谷Bioon.com)

Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis

Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, Berndt SI, B¨¦zieau S, Brenner H, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Chen LS, Coetzee GA, Coetzee SG, Conti DV, Curtis KR, Duggan D, Edwards T, Fuchs CS, Gallinger S, Giovannucci EL, Gogarten SM, Gruber SB, Haile RW, Harrison TA, Hayes RB, Henderson BE, Hoffmeister M, Hopper JL, Hudson TJ, Hunter DJ, Jackson RD, Jee SH, Jenkins MA, Jia WH, Kolonel LN, Kooperberg C, K¨¹ry S, Lacroix AZ, Laurie CC, Laurie CA, Le Marchand L, Lemire M, Levine D, Lindor NM, Liu Y, Ma J, Makar KW, Matsuo K, Newcomb PA, Potter JD, Prentice RL, Qu C, Rohan T, Rosse SA, Schoen RE, Seminara D, Shrubsole M, Shu XO, Slattery ML, Taverna D, Thibodeau SN, Ulrich CM, White E, Xiang Y, Zanke BW, Zeng YX, Zhang B, Zheng W, Hsu L; Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium.

BACKGROUND & AIMS: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 ¡Á 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 ¡Á 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 ¡Á 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 ¡Á 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 ¡Á 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 ¡Á 10(-7)). CONCLUSIONS: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to ¦Â-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

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