Department of Colorectal Surgery, Singapore General Hospital, Singapore, Singapore.
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
J Med Genet. 2018 Mar;55(3):181-188. doi: 10.1136/jmedgenet-2017-104913. Epub 2017 Oct 27.
Multiple single nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) risk. The role of structural or copy number variants (CNV) in CRC, however, remained unclear. We investigated the role of CNVs in patients with sporadic CRC.
A genome-wide association study (GWAS) was performed on 1000 Singapore Chinese patients aged 50 years or more with no family history of CRC and 1000 ethnicity-matched, age-matched and gender-matched healthy controls using the Affymetrix SNP 6 platform. After 16 principal component corrections, univariate and multivariate segmentations followed by association testing were performed on 1830 samples that passed quality assurance tests.
A rare CNV region (CNVR) at chromosome 14q11 (OR=1.92 (95% CI 1.59 to 2.32), p=2.7e-12) encompassing , and common CNVR at chromosomes 3q13.12 (OR=1.54 (95% CI 1.33 to 1.77), p=2.9e-9) and 12p12.3 (OR=1.69 (95% CI 1.41 to 2.01), p=2.8e-9) encompassing and /, respectively, were significantly associated with CRC risk. CNV loci were validated in an independent replication panel using an optimised copy number assay. Whole-genome expression data in matched tumours of a subset of cases demonstrated that copy number loss at was significantly associated with dysregulation of several genes that perturb the , and inflammatory pathways.
A rare CNVR at 14q11 encompassing the chromatin modifier was significantly associated with sporadic CRC risk. Copy number loss at altered expressions of genes implicated in colorectal tumourigenesis.
多个单核苷酸多态性（SNP）与结直肠癌（CRC）风险相关。然而，结构性或拷贝数变异（CNV）在 CRC 中的作用仍不清楚。我们研究了 CNV 在散发性 CRC 患者中的作用。
使用 Affymetrix SNP 6 平台，对 1000 名年龄在 50 岁或以上、无 CRC 家族史的新加坡华人患者和 1000 名年龄、性别匹配的健康对照者进行全基因组关联研究（GWAS）。经过 16 个主成分校正后，对通过质量保证测试的 1830 个样本进行单变量和多变量分割，然后进行关联测试。
染色体 14q11 上的一个罕见 CNV 区域（CNVR）（OR=1.92（95%置信区间 1.59 至 2.32），p=2.7e-12）包含，以及染色体 3q13.12（OR=1.54（95%置信区间 1.33 至 1.77），p=2.9e-9）和 12p12.3（OR=1.69（95%置信区间 1.41 至 2.01），p=2.8e-9）包含和/，分别与 CRC 风险显著相关。CNV 位置在使用优化拷贝数检测的独立复制面板中得到验证。病例亚组匹配肿瘤的全基因组表达数据表明，的拷贝数缺失与扰乱、和炎症途径的几个基因的失调显著相关。
染色体 14q11 上的罕见 CNVR 与散发性 CRC 风险显著相关。的拷贝数缺失改变了结直肠肿瘤发生中涉及的基因的表达。
