Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, USA, Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, RI, USA,
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
Carcinogenesis. 2014 Dec;35(12):2698-705. doi: 10.1093/carcin/bgu203. Epub 2014 Sep 19.
The chromosome 9p21 region has been implicated in the pathogenesis of multiple cancers. We analyzed 9p21 single nucleotide polymorphisms (SNPs) from eight genome-wide association studies (GWAS) with data deposited in dbGaP, including studies of esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer (LC), breast cancer (BrC), bladder cancer (BC) and prostate cancer (PrC). The number of subjects ranged from 2252 (PrC) to 7619 (LC). SNP-level analyses for each cancer were conducted by logistic regression or random-effects meta-analysis. A subset-based statistical approach (ASSET) was performed to combine SNP-level P values across multiple cancers. We calculated gene-level P values using the adaptive rank truncated product method. We identified that rs1063192 and rs2157719 in the CDKN2A/2B region were significantly associated with ESCC and rs2764736 (3' of TUSC1) was associated with BC (P ≤ 2.59 × 10(-6)). ASSET analyses identified four SNPs significantly associated with multiple cancers: rs3731239 (CDKN2A intronic) with ESCC, GC and BC (P = 3.96 × 10(-) (4)); rs10811474 (3' of IFNW1) with RCC and BrC (P = 0.001); rs12683422 (LINGO2 intronic) with RCC and BC (P = 5.93 × 10(-) (4)) and rs10511729 (3' of ELAVL2) with LC and BrC (P = 8.63 × 10(-) (4)). At gene level, CDKN2B, CDKN2A and CDKN2B-AS1 were significantly associated with ESCC (P ≤ 4.70 × 10(-) (5)). Rs10511729 and rs10811474 were associated with cis-expression of 9p21 genes in corresponding cancer tissues in the expression quantitative trait loci analysis. In conclusion, we identified several genetic variants in the 9p21 region associated with the risk of multiple cancers, suggesting that this region may contribute to a shared susceptibility across different cancer types.
9p21 染色体区域与多种癌症的发病机制有关。我们分析了来自 8 项全基因组关联研究（GWAS）的 9p21 单核苷酸多态性（SNP）数据，这些数据已存入 dbGaP，包括食管鳞状细胞癌（ESCC）、胃癌（GC）、胰腺癌、肾细胞癌（RCC）、肺癌（LC）、乳腺癌（BrC）、膀胱癌（BC）和前列腺癌（PrC）的研究。研究对象的数量从 2252 人（PrC）到 7619 人（LC）不等。通过逻辑回归或随机效应荟萃分析对每种癌症进行 SNP 水平分析。采用基于亚组的统计方法（ASSET）对多种癌症的 SNP 水平 P 值进行合并。我们使用自适应秩截断乘积方法计算基因水平 P 值。我们发现 CDKN2A/2B 区域的 rs1063192 和 rs2157719 与 ESCC 显著相关，rs2764736（TUSC1 3'）与 BC 相关（P≤2.59×10^(-6)）。ASSET 分析确定了与多种癌症显著相关的四个 SNP：rs3731239（CDKN2A 内含子）与 ESCC、GC 和 BC 相关（P=3.96×10^(-6)（4））；rs10811474（IFNW1 3'）与 RCC 和 BrC 相关（P=0.001）；rs12683422（LINGO2 内含子）与 RCC 和 BC 相关（P=5.93×10^(-6)（4））；rs10511729（ELAVL2 3'）与 LC 和 BrC 相关（P=8.63×10^(-6)（4））。在基因水平上，CDKN2B、CDKN2A 和 CDKN2B-AS1 与 ESCC 显著相关（P≤4.70×10^(-6)（5））。rs10511729 和 rs10811474 与相应癌症组织中 9p21 基因的顺式表达相关，在表达数量性状基因座分析中。总之，我们在 9p21 区域发现了一些与多种癌症风险相关的遗传变异，表明该区域可能导致不同癌症类型的共同易感性。
