Elsevier

Leukemia Research

Volume 34, Issue 10, October 2010, Pages 1271-1274
Leukemia Research

Genome-wide association study of childhood acute lymphoblastic leukemia in Korea

https://doi.org/10.1016/j.leukres.2010.02.001Get rights and content

Abstract

We conducted a genome-wide association study of childhood acute lymphoblastic leukemia (ALL) in a case–control study conducted in Korea. Incident childhood ALL cases (n = 50) and non-cancer controls (n = 50) frequency-matched to cases by age and sex, recruited from three teaching hospitals in Seoul between 2003 and 2008, were genotyped using Affymetrix SNP Array 6.0 platform. ALL risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age and birth weight. The false discovery rate (FDR) was used for adjusting multiple tests. Of these 1 million SNPs, six SNPs in 4 genes (HAO1 rs6140264, EPB41L2 rs9388856, rs9388857, rs1360756, C2orf3 12105972, MAN2A1 rs3776932) were strongly associated with childhood ALL risk (Pdominant  0.0001 and Ptrend < 0.006). These SNPs remained significant after FDR adjustment (FDR value <0.2). Our genome-wide association study in Korea children identified a few genetic variations as potential susceptibility markers for ALL, warranting further replication studies among various ethnic groups.

Introduction

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, accounting for 30% of all childhood cancers [1]. The etiology of childhood ALL is mostly unknown, although infections in the first years of life and some environmental factors such as ionizing radiation and parental alcohol and tobacco use could play a causative role in ALL [2], [3], [4].

ALL is known to result from an accumulation of mutations in tumor suppressor genes and oncogenes, and genetic alterations affecting several chromosomes [5], [6], [7], [8], [9]. Although common genetic variations may play a role in determining individual susceptibility of leukemia development in children, limited studies have evaluated the association between genetic polymorphisms in candidate genes such as CYP, GST, NAT, MTHFR, NQO1, XRCC1, MDR1, cyclin D1, and CCND1 and childhood ALL risk [1], [10], [11], [12].

Given that investigation of a single enzyme (pathway) and/or a single genotype might not be sufficient to explain the etiology of childhood leukemia [11], a genome-wide approach may add to comprehensive knowledge about genetic susceptibility to childhood ALL.

In this context, we conducted a genome-wide association study (GWAS) to identify genetic variations associated with childhood ALL in our Korean Childhood Leukemia Study.

Section snippets

Subjects

The detailed information on selection criteria of the subjects and data collection was described elsewhere [13]. Histologically confirmed incident childhood ALL cases (n = 201) aged 0–18 years old were recruited from three teaching hospitals located in Seoul, Korea, between May 2003 and August 2008. Non-cancer controls (n = 558) aged 0–18 years old without medical history of childhood cancer were recruited from the Department of Pediatrics of the same hospitals. Participation rate was approximately

Results

There was no significant difference of the selected characteristics between case and control group except for birth weight: higher birth weight was associated with increased risk of childhood ALL (3.25–3.70 vs. ≤3.25 kg: OR = 6.04, 95% CI = 2.04–17.01; >3.70 vs. ≤3.25 kg: OR = 4.56, 95% CI = 1.53-13.52; Ptrend = 0.001, data not shown). Fig. 1 shows P values on a logarithmic scale from trend tests for 681,931 selected variants.

Among the 681,931 SNPs, 57,173 SNPs in 7,791 genes had a Ptrend < 0.05 from

Discussion

In our genome-wide association study, 6 novel SNPs in 4 genes in childhood ALL using Affymetrix SNP Array 6.0 platform were associated with childhood ALL (HAO1: rs6140264; EPB41L2: rs9388856, rs9388857, and rs1360756, C2orf3: rs12105972; MAN2A1: rs3776932).

Although our observation should be interpreted cautiously due to limited biological plausibility for the observed association between those SNPs and childhood ALL risk, we note that erythrocyte membrane protein band 4.1-like 2 (EPB41L) plays

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

The authors thank all patients and their parents who consented to participate in genetics study related to leukemia.

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, R.O.K. (AO30001) and a grant No. R31-2008-000-10103-0 from the WCU project of the MEST and the NRF.

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