Authors' Affiliations: Department of Surgery, Division of Surgical Oncology, Center for Genomic Medicine, Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts; Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California; Department of Epidemiology and Statistics, Memorial Sloan-Kettering Cancer Center, New York; RIKEN Center for Genomic Medicine, Tokyo, Japan; Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh; Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom; Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville; Genetic and Molecular Epidemiology Laboratories, and Familial Cancer laboratory, Queensland Institute of Medical Research, Brisbane; Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; and Department of Medicine, University of Chicago, Chicago, Illinois.
Clin Cancer Res. 2013 Dec 1;19(23):6430-7. doi: 10.1158/1078-0432.CCR-13-0550. Epub 2013 Oct 1.
Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas.
Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10(-7). Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58].
Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10(-7) level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r(2) = 0.8-1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50-2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211).
Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance.
鉴定与结直肠腺瘤进展相关的单核苷酸多态性（SNP）。
发现阶段：1406 名高加索患者（139 例进展性腺瘤病例和 1267 例对照）纳入塞来昔布预防腺瘤（APC）试验的全基因组关联研究（GWAS），以鉴定与息肉切除术后疾病复发相关的变异。全基因组显著水平定义为错误发现率小于 0.05，未调整的 P = 7.4×10(-7)。验证阶段：使用来自欧洲血统的 4175 例家族性结直肠腺瘤病例和 5036 例对照（COloRectal Gene Identification 联盟（CORGI），苏格兰、澳大利亚和 VQ58）进一步评估结果。
我们的研究在 APC 试验中鉴定出 8 个与进展性腺瘤风险相关的 SNP(rs2837156、rs7278863、rs2837237、rs2837241、rs2837254、rs741864 在 21q22.2 处，rs1381392 和 rs17651822 在 3p24.1 处，P<10(-7)，OR>2)。5 个强连锁不平衡(rs7278863、rs2837237、rs741864、rs741864 和 rs2837241；r(2)=0.8-1)的变体位于或靠近紧密连接粘附蛋白 IGSF5 的编码区。另一个与进展性腺瘤相关的变异 rs1535989[次要等位基因频率 0.11；OR 2.09；95%置信区间（CI）1.50-2.91]，在使用一系列腺瘤病例或结直肠癌（CORGI 研究）和 3 组结直肠癌病例和对照（苏格兰、VQ58 和澳大利亚；N=9211）的验证分析中也预测了结直肠癌的发展（P=0.019）。
我们的研究结果表明，常见的多态性有助于进展性腺瘤的风险，也可能有助于结直肠癌的风险。rs1535989 处的变异可能会识别出那些需要增加结肠镜检查监测的肿瘤风险患者。
