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Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

ABSTRACT: Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P?=?3.86?×?10-9, odds ratio (OR)?=?1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P?=?3.20?×?10-8, OR?=?2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.

SUBMITTER: Vijayakrishnan J

PROVIDER: S-EPMC5890276 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

Vijayakrishnan Jayaram J Studd James J Broderick Peter P Kinnersley Ben B Holroyd Amy A Law Philip J PJ Kumar Rajiv R Allan James M JM Harrison Christine J CJ Moorman Anthony V AV Vora Ajay A Roman Eve E Rachakonda Sivaramakrishna S Kinsey Sally E SE Sheridan Eamonn E Thompson Pamela D PD Irving Julie A JA Koehler Rolf R Hoffmann Per P Nöthen Markus M MM Heilmann-Heimbach Stefanie S Jöckel Karl-Heinz KH Easton Douglas F DF Pharaoh Paul D P PDP Dunning Alison M AM Peto Julian J Canzian Frederico F Swerdlow Anthony A Eeles Rosalind A RA Kote-Jarai ZSofia Z Muir Kenneth K Pashayan Nora N Greaves Mel M Zimmerman Martin M Bartram Claus R CR Schrappe Martin M Stanulla Martin M Hemminki Kari K Houlston Richard S RS

Nature communications 20180409 1

Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10<sup>-9</sup>, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, ...[more]

PMID: 29632299

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Project description:Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P?<0.05).The statistically most significant sex-specific association (P?=?4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ? 14; P?<0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

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Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

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Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.

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