Ross Jason, Lockett Linda, Brookes Diana, Tabor Bruce, Duesing Konsta, Buckley Michael, Lockett Trevor, Molloy Peter, Macrae Finlay, Young Graeme, Blanco Ignacio, Capella Gabriel, Hannan Garry N
1] CSIRO, Preventative Health National Research Flagship, North Ryde, NSW, Australia [2] Animal, Food and Health Sciences, CSIRO, North Ryde, NSW, Australia.
Eur J Hum Genet. 2013 Dec;21(12):1389-95. doi: 10.1038/ejhg.2013.53. Epub 2013 Mar 27.
Recently our group completed a genome-wide linkage study investigating Australian and Spanish families with inherited risk of colorectal cancer (CRC). A minor linkage peak from that study located on chromosome 1 correlates with the location of a known CRC risk-modifying gene, prostaglandin synthase (PTGS2). PTGS2 encodes the inducible prostaglandin synthase enzyme cyclooxygenase-2 (COX-2). Prostaglandins are implicated in the initiation of carcinogenesis and progression of tumours. Sequencing of PTGS2 in a small subset of affected individuals identified a high frequency of the minor C allele of single nucleotide polymorphism rs5275. We then genotyped the rs5275 polymorphism in 183 affected and 223 unaffected individuals from our CRC predisposed families. Tests for association in the presence of linkage were made using family-based association tests. The C allele was found to be significantly associated (P<0.01) with diagnosis of hereditary non-syndromic CRC (P=0.0094, dominant model) and an earlier age of diagnosis (P=0.0089, heterozygous-advantage model). Interestingly, by stratifying the age of diagnosis data, we observed a speculative gender-discordant effect. Relative to other groups, female CC carriers were diagnosed less when young, but by 60 years of age were the most at risk group. Conversely, CT carriers of both genders showed a consistently earlier diagnosis relative to TT carriers. Our results suggest potential differential age-and gender-dependent efficacies of chemopreventative COX-2 inhibitors in the context of non-syndromic colorectal cancer.
最近，我们团队完成了一项全基因组连锁研究，调查有遗传性结直肠癌（CRC）风险的澳大利亚和西班牙家庭。该研究中位于1号染色体上的一个较小的连锁峰与已知的CRC风险修饰基因前列腺素合酶（PTGS2）的位置相关。PTGS2编码诱导型前列腺素合酶环氧合酶-2（COX-2）。前列腺素与肿瘤发生的起始和肿瘤进展有关。在一小部分受影响个体中对PTGS2进行测序，发现单核苷酸多态性rs5275的次要C等位基因频率很高。然后，我们对来自CRC易感家庭的183名受影响个体和223名未受影响个体的rs5275多态性进行了基因分型。使用基于家系的关联测试在存在连锁的情况下进行关联测试。发现C等位基因与遗传性非综合征性CRC的诊断（P=0.0094，显性模型）和更早的诊断年龄（P=0.0089，杂合优势模型）显著相关（P<0.01）。有趣的是，通过对诊断年龄数据进行分层，我们观察到一种推测性的性别不一致效应。相对于其他组，女性CC携带者在年轻时诊断较少，但到60岁时是风险最高的组。相反，两性的CT携带者相对于TT携带者显示出一致更早的诊断。我们的结果表明，在非综合征性结直肠癌的背景下，化学预防COX-2抑制剂可能存在年龄和性别依赖性的差异疗效。
