Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia

Sherborne, Amy L.; Hemminki, Kari; Kumar, Rajiv; Bartram, Claus R.; Stanulla, Martin; Schrappe, Martin; Petridou, Eleni; Semsei, Ágnes F.; Szalai, Csaba; Sinnett, Daniel; Krajinović, Maja; Healy, Jasmine; Lanciotti, Marina; Dufour, Carlo; Indaco, Stefania; El-Ghouroury, Eman A.; Sawangpanich, Ruchchadol; Hongeng, Suradej; Pakakasama, Samart; González-Neira, Anna; Ugarte, Evelia L.; Leal, Valeria P.; Espinoza, Juan Pablo Meza; Kamel, Azza M.; Ebid, Gamal; Radwan, Eman R.; Yalın, Serap; Yalın, Erdinç; Berköz, Mehmet; Simpson, Jill; Roman, Eve; Lightfoot, Tracy; Hosking, Fay J.; Vijayakrishnan, Jayaram; Greaves, Mel; Houlston, Richard S.

doi:10.3324/haematol.2011.040121

Cited by 36 publications

(29 citation statements)

References 31 publications

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“…Analysis of additional ongoing GWAS of BCP-ALL, which are based on higher-density array technology are therefore likely to be informative in refining estimates of heritability. Further advancements are likely to be made following the establishment of large consortia, 18 including the Childhood Leukemia International Consortium. Such initiatives not only provide the basis for GWA studies with increased sample size, SNP coverage and number of SNPs taken forward to large-scale replication to aid in the identification of additional novel risk variants, but also facilitate pooling studies of existing GWAS data to importantly improve the standard error of the point estimate of the heritability of BCP-ALL.…”

Section: Discussionmentioning

confidence: 99%

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia

et al. 2012

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Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants.

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Section: Discussionmentioning

confidence: 99%

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia

et al. 2012

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“…13 The identification and analysis of such low-penetrance variants may further facilitate the pathogenetic understanding of pediatric and adult ALL. Last, but not least, it has to be kept in mind that ethnic background may influence the risk and thus the hitherto reported risk factors may not be valid for all regions of the world.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group

et al. 2014

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Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group A number of single nucleotide polymorphisms (SNPs) in the genes IKZF1, ARID5B, CEBPE and CDKN2A have been implicated in the propensity to develop acute lymphoblastic leukemia (ALL) in childhood (< 15 years of age)1-4 but since the genetic background of adult and childhood ALL is different, it is not clear if these are also risk factors for adult-onset ALL. We analyzed seven SNPs (two in IKZF1: rs11978267, rs4132601; three in ARID5B: rs10821936, rs10994982, rs7089424; and one each in CEBPE: rs2239633 and CDKN2A: rs3731217) which were reported to confer an increased risk for childhood ALL in 322 immunologically and genetically well-characterized adult or adolescent ALL patient samples. All samples were obtained from BCR-ABL-negative patients at time points when they were in molecular remission, thus excluding mutations acquired during onset of disease and randomly selected from a large collection of archived samples obtained during diagnostic procedures in the framework of the German Multicenter ALL Study Group (GMALL) trial 07/2003 (Clinicaltrials.gov identifier:00198991). This trial has been approved by various local and central ethics committees and our study complied with the principles set forth in the Declaration of Helsinki. The median age of the patient cohort was 38 years (range 16-76 years), and 58.4% of the patients were male. Flow cytometry immunophenotyping and molecular genetic analyses for BCR-ABL, MLL-AF4, MLL-ENL, TCF3-PBX1, and ETV6-RUNX1 were performed at primary diagnosis as described previously.5,6 Assessment of minimal residual disease was made as described. Patient samples were selected in such a way as to match the distribution of immunophenotypes observed in the last ten years in the GMALL study group, thereby taking into consideration that BCR-ABL-positive patients had been excluded (Table 1).The control group comprised a total of 1516 healthy individuals of German origin collected through 2004 at the Institute of Transfusion Medicine in Mannheim, Germany (genotyped for rs4132601, rs7089424, rs2239633, rs3731217). 4,9 Since no German control data were available for ARID5B rs10994982, this SNP was compared to a cohort comprising 14,311 individuals of European descent without ALL, collected by the Wellcome Trust Case Control Consortium (WTCCC); these results are only reported for completeness and are not listed in Table 2.10 Details of the control groups have been described previously. Supplementary Appendix). Therefore, rs11978267 and rs10821936 were not considered in further analysis since they added nothing new.The observed allele frequencies are summarized in Table 2. All presumed "risk alleles" were more frequent in B-lineage ALL patients as compared to non-ALL controls while there was no difference in frequencies in T-lineage ALL. For the following genotypes, the differences were statistically significant in B-lineage ALL patients: 0E-03), ...

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“…Undetected associations due to insufficient sample sizes, which pertain to both genome-wide and candidate gene studies, is a central issue underscored by both the EncisoMora et al report [6] and previous reviews [5,104]. Power calculations have shown that even the largest GWAS conducted to date (907 cases and 2,398 controls) had limited ability to detect variants conferring relative risks of 1.4 or below and/or those with allele frequencies of \0.10 [6,104].…”

Section: Areas Of Ongoing and Future Workmentioning

confidence: 99%

Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia

et al. 2012

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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.

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Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia

Cited by 36 publications

References 31 publications

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia

Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group

Current evidence for an inherited genetic basis of childhood acute lymphoblastic leukemia

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