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

Enciso-Mora,; Hosking, Fay J.; Sheridan, Eamonn; Kinsey, Sally; Lightfoot, Tracy; Roman, Eve; Irving, Julie; Tomlinson, Ian; Allan, James M.; Taylor, Malcolm; Greaves, Mel; Houlston, Richard S.

doi:10.1038/leu.2012.89

Cited by 38 publications

(30 citation statements)

References 19 publications

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“…23 Nonetheless, the range of the posterior on PVE nicely spans the estimates provided by the other methods equally to both sides, proving the ability of the PVE method to quantify uncertainty in multivariate problems by assessing the full joint posterior distribution of the model parameters compared Heritability estimates on Hodgkin's lymphoma H Thomsen et al with the current simplistic 'one SNP at a time' testing paradigm, 34,35 because analyzing all SNPs simultaneously will detect more of the genetic variation because of the identification of multiple causal variants. 36 In contrast to the results of Enciso-Mora et al, 37 our estimates of the variance are almost constant across the different numbers of SNPs and do not decline after a more stringent exclusion of missing genotypes. This is in agreement with the results by Yang et al 19 and Lee et al 38 Thus, our QC has been stringent enough beforehand.…”

Section: Discussioncontrasting

confidence: 55%

Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

et al. 2014

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Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of Hodgkin's lymphoma (HL) and demonstrated the association of common genetic variation for this type of cancer. Such evidence for inherited genetic risk is also provided by the family history and the very high concordance between monozygotic twins. However, little is known about the genetic and environmental contributions. A common measure for describing the phenotypic variation due to genetics is the heritability. Using GWAS data on 906 HL cases by considering all typed SNPs simultaneously, we have calculated that the common variance explained by SNPs accounts for 435% of the total variation on the liability scale in HL (95% confidence interval 6-62%). These findings are consistent with similar heritability estimates of ∼ 0.40 (95% confidence interval 0.17-0.58) based on Swedish population data. Our estimates support the underlying polygenic basis for susceptibility to HL, and show that heritability based on the population data is somehow larger than heritability based on the genomic data because of the possibility of some missing heritability in the GWAS data. Besides that there is still major evidence for multiple loci causing HL on chromosomes other than chromosome 6 that need to be detected. Because of limited findings in prior GWASs, it seems worth checking for more loci causing susceptibility to HL.

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Section: Discussioncontrasting

confidence: 55%

Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

et al. 2014

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“…Although GWAS are widely recognized as rigorous in their approach to identifying disease loci [101], the P value requirements for defining a significant association, in return, increases the probability of missing a true association as recently demonstrated specifically in childhood leukemia. Using previously derived methods [102,103] applied to an analysis of nearly 250,000 SNP genotypes from the UK GWAS [79], Enciso-Mora et al [6] estimated that about 24 % of the total variation in childhood B-cell precursor ALL risk is accounted for by common genetic variation, and the previously identified loci (IKZF1, ARID5B, CEBPE, and CDKN2A) explain only 8 % of this total. This study provides evidence for a polygenic mechanism of susceptibility and rationale for continued investigation of additional susceptibility loci that were likely missed by previous GWAS.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…The early age of onset of childhood ALL suggests that inherited genetic traits may play a role, and recent evidence indicates that these contribute to a substantial proportion of the variation in childhood ALL risk [5,6]. Such genetic traits can range from predisposing rare highly penetrant mutations to more common low penetrance genetic polymorphisms.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, has a significant genetic basis for susceptibility (1)(2)(3)(4). As well as contributing to the risk of childhood ALL, inherited genetic variation appears to predispose to specific ALL subtypes and response to chemotherapeutic intervention (2).…”

Section: Introductionmentioning

confidence: 99%

Folate Pathway Gene Polymorphisms, Maternal Folic Acid Use, and Risk of Childhood Acute Lymphoblastic Leukemia

Milne

Greenop

Scott

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003)(2004)(2005)(2006)(2007).Methods: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched vari-

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

Cited by 38 publications

References 19 publications

Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

Heritability estimates on Hodgkin’s lymphoma: a genomic- versus population-based approach

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

Folate Pathway Gene Polymorphisms, Maternal Folic Acid Use, and Risk of Childhood Acute Lymphoblastic Leukemia

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