一项对标签单核苷酸多态性的全基因组关联扫描在8q24.21区域发现了一个结直肠癌的易感性变异。

A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

作者信息

Tomlinson Ian, Webb Emily, Carvajal-Carmona Luis, Broderick Peter, Kemp Zoe, Spain Sarah, Penegar Steven, Chandler Ian, Gorman Maggie, Wood Wendy, Barclay Ella, Lubbe Steven, Martin Lynn, Sellick Gabrielle, Jaeger Emma, Hubner Richard, Wild Ruth, Rowan Andrew, Fielding Sarah, Howarth Kimberley, Silver Andrew, Atkin Wendy, Muir Kenneth, Logan Richard, Kerr David, Johnstone Elaine, Sieber Oliver, Gray Richard, Thomas Huw, Peto Julian, Cazier Jean-Baptiste, Houlston Richard

机构信息

Molecular and Population Genetics Laboratory, Cancer Research UK, London WC2A 3PX, UK.

出版信息

Nat Genet. 2007 Aug;39(8):984-8. doi: 10.1038/ng2085. Epub 2007 Jul 8.

DOI:10.1038/ng2085

PMID:17618284

Abstract

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

摘要

遗传性结直肠癌（CRC）风险的大部分变异可能是由于常见低风险变异的组合所致。我们对930例家族性结直肠肿瘤病例和960例对照中的550,000个标签单核苷酸多态性（SNP）进行了全基因组关联研究。最显著相关的SNP（等位基因检验，P = 1.72 x 10(-7)）是位于8q24.21的rs6983267。为验证这一发现，我们在另外三个CRC病例对照系列中对rs6983267进行基因分型（4,361例患者和3,752例对照；1,901例患者和1,079例对照；1,072例患者和415例对照），并重复了该关联，总体等位基因检验P = 1.27 x 10(-14)，杂合子和罕见纯合子的优势比（OR）分别为1.27（95%置信区间（c.i.）：1.16 - 1.39）和1.47（95% c.i.：1.34 - 1.62）。基于1,477例大肠腺瘤患者和2,136例对照的分析表明，对CRC的易感性是通过腺瘤的发生介导的（OR = 1.21，95% c.i.：1.10 - 1.34；P = 6.89 x 10(-5)）。这些数据表明，常见的、低外显率的易感等位基因易导致结直肠肿瘤形成。