Genetic Variants Modify Susceptibility to Leukemia in Infants: A Children's Oncology Group Report
ABSTRACT BACKGROUND: The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE. PROCEDURE: We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements. RESULTS: Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633). CONCLUSION: IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
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ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and efforts to understand its etiology has followed a paradigm that common genetic variation in the presence of modifiable environmental factors contribute to disease risk. To date, there are numerous reports of candidate gene association studies suggesting an involvement of genetic loci in childhood ALL risk, but the general lack of consistency in results has underscored the need for careful interpretation and confirmation in additional well-designed studies. Complementary efforts using the genome-wide association study approach have shown indisputable evidence that common low penetrance genetic polymorphisms contribute to childhood ALL risk. However, current calculations show that these established disease loci only explain a portion of the total estimated contribution of common genetic variation on childhood ALL risk. Certain candidate gene loci previously examined likely contribute to this unexplained variation in risk, but the challenge moving forward will be to establish which ones based on the accumulating evidence. In this review, we describe the results of the most recent gene association studies in childhood ALL and discuss options for future efforts to advance this area of research.International journal of hematology 12/2012; 97(1). DOI:10.1007/s12185-012-1220-9 · 1.68 Impact Factor
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ABSTRACT: The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL.01/2013; 3(1):1-13.
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ABSTRACT: Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios ≥1.33, Ptrend≤0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction≥0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction≥0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.Leukemia research 05/2013; 37(8). DOI:10.1016/j.leukres.2013.04.022 · 2.69 Impact Factor