Department of Clinical Pharmacology, University of Oxford, Headington, Oxford, UK.
J Hum Genet. 2011 Jan;56(1):58-63. doi: 10.1038/jhg.2010.144. Epub 2010 Nov 25.
We examined the influence that rare variants and low-frequency polymorphisms in the cancer candidate gene CCND1 have on the development of multiple intestinal adenomas and the early onset of colorectal cancer. Individuals with <100 multiple polyps and patients with colorectal cancer diagnosed before 50 years of age were recruited in UK, and screened for sequence changes in the coding and regulatory regions of CCND1. A set of about 800 UK control individuals was genotyped for the variants discovered in the cases. Variants in the promoter, intron-exon boundaries and untranslated regions of the CCND1 gene had higher frequencies in cases than in controls. Five of these variants were typed in a set of French multiple adenoma and early-onset patients, who also showed higher allele frequencies than UK controls. When pooled together, variants with frequencies lower than 1% conferred an increased risk of disease that was significant in the multiple adenoma group (odds ratio (OR) 2.2; 95% confidence interval, 1.1-4.4; P = 0.03). Most variants had a putative functional effect when assessed in silico. We conclude that rare variants of CCND1 are risk factors for colorectal cancer, with considerably larger effects than common polymorphisms, and as such should be systematically evaluated in susceptibility studies.
我们研究了癌症候选基因 CCND1 中的罕见变异和低频多态性对多发性肠腺瘤的发生和结直肠癌的早期发病的影响。在英国，我们招募了患有 <100 个多发性息肉的个体和 50 岁前被诊断为结直肠癌的患者，并对 CCND1 编码区和调控区的序列变化进行了筛选。我们对病例中发现的变异对大约 800 名英国对照个体进行了基因分型。在 CCND1 基因的启动子、内含子-外显子边界和非翻译区的变异在病例中比对照中更常见。这些变体中的五个在一组法国多发性腺瘤和早发患者中进行了分型，他们的等位基因频率也高于英国对照。当汇总在一起时，频率低于 1%的变体在多发性腺瘤组中具有显著的疾病风险增加（比值比 (OR) 2.2；95%置信区间，1.1-4.4；P = 0.03）。当通过计算机进行评估时，大多数变体具有假定的功能效应。我们的结论是，CCND1 的罕见变异是结直肠癌的危险因素，其作用明显大于常见多态性，因此应在易感性研究中系统评估。
