Vijayakrishnan J, Kumar R, Henrion M Y R, Moorman A V, Rachakonda P S, Hosen I, da Silva Filho M I, Holroyd A, Dobbins S E, Koehler R, Thomsen H, Irving J A, Allan J M, Lightfoot T, Roman E, Kinsey S E, Sheridan E, Thompson P D, Hoffmann P, Nöthen M M, Heilmann-Heimbach S, Jöckel K H, Greaves M, Harrison C J, Bartram C R, Schrappe M, Stanulla M, Hemminki K, Houlston R S
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
Leukemia. 2017 Mar;31(3):573-579. doi: 10.1038/leu.2016.271. Epub 2016 Oct 3.
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.
全基因组关联研究（GWAS）表明，常见的基因变异会导致儿童急性淋巴细胞白血病（ALL）的遗传易感性。为了确定ALL最大亚型即B细胞前体ALL（BCP-ALL）的新易感基因座，我们使用千人基因组计划和英国十万人基因组计划的数据作为参考，对两项进行了插补的GWAS进行了荟萃分析（共1658例病例和7224例对照）。在对另外2525例病例和3575例对照进行基因分型后，我们确定了BCP-ALL的新易感基因座，分别定位于10q26.13（rs35837782，LHPP，P = 1.38×10）和12q23.1（rs4762284，ELK3，P = 8.41×10）。我们还为9p21.3处存在独立风险基因座提供了确证，但表明rs77728904标记的关联可由与罕见的高影响CDKN2A p.Ala148Thr变异体rs3731249的连锁不平衡来解释。我们的数据为ALL的遗传易感性及其生物学特性提供了进一步的见解。
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