Walsh Kyle M, de Smith Adam J, Hansen Helen M, Smirnov Ivan V, Gonseth Semira, Endicott Alyson A, Xiao Jianqiao, Rice Terri, Fu Cecilia H, McCoy Lucie S, Lachance Daniel H, Eckel-Passow Jeanette E, Wiencke John K, Jenkins Robert B, Wrensch Margaret R, Ma Xiaomei, Metayer Catherine, Wiemels Joseph L
Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
Cancer Res. 2015 Nov 15;75(22):4884-94. doi: 10.1158/0008-5472.CAN-15-1105. Epub 2015 Nov 2.
Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case-control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10(-9)) and Hispanic children (OR, 2.77; P = 3.78 × 10(-4)). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS "hits" and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors.
全基因组关联研究（GWAS）已经在六个基因中鉴定出与儿童急性淋巴细胞白血病（ALL）相关的单核苷酸多态性（SNP）。发现一个主要SNP位于9号染色体p21.3区域，该区域在30%的儿童ALL中发生缺失，这表明存在与ALL风险相关的因果多态性。我们对一个多民族ALL病例对照人群（病例数=1464，对照数=3279）进行SNP基因分型和基于归因的精细定位，以鉴定9p21.3区域内具有大效应的变异。我们鉴定出一个CDKN2A错义变异（rs3731249），在对照中的等位基因频率为2%，该变异使欧洲血统儿童患ALL的风险增加三倍（比值比，2.99；P=1.51×10⁻⁹），西班牙裔儿童患ALL的风险也增加三倍（比值比，2.77；P=3.78×10⁻⁴）。此外，在17例肿瘤在CDKN2A处显示等位基因不平衡的患者中，有14例优先保留风险等位基因并丢失保护性等位基因（二项式P=0.006），这表明风险等位基因在肿瘤生长过程中提供了选择性优势。值得注意的是，CDKN2A变异与黑色素瘤、胶质母细胞瘤或胰腺癌风险无显著关联，这意味着这种多态性特异性地赋予ALL风险，而不是一般癌症风险。综上所述，我们的研究结果表明，具有大效应的编码多态性可能是GWAS“命中”的基础，并且遗传多态性可能在肿瘤的克隆扩增过程中经历定向选择。
