Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia

Papaemmanuil, Elli; Hosking, Fay J.; Vijayakrishnan, Jayaram; Price, Amy; Olver, Bianca; Sheridan, Eammon; Kinsey, Sally; Lightfoot, Tracy; Roman, Eve; Irving, Julie; Allan, James M.; Tomlinson, Ian; Taylor, Malcolm; Greaves, Mel; Houlston, Richard S.

doi:10.1038/ng.430

Cited by 431 publications

(488 citation statements)

References 22 publications

(21 reference statements)

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“…Thus far, GWAS of ALL, including the parent study on which this current analysis is based, have identified four independent loci shown conclusively to be associated with ALL, and more specifically BCP-ALL risk-7p12.2 (IKZF1), 9p12 (CDKN2A/CDKN2B), 10q21.2 (ARID5B) and 14q11.2 (CEBPE). [4][5][6] While the risk of ALL associated with these common variants is not insignificant (RRs of 1.5-1.6), collectively they only underscore B8% of the genetic variance in BCP-ALL risk.…”

Section: Discussionmentioning

confidence: 94%

“…4,6 Briefly, we analyzed 824 pediatric BCP-ALL patients ascertained from the United Kingdom (UK; 464 male, 360 female; mean age at diagnosis 5.4 years, s.d. ¼ 3.6), derived from the United Kingdom Childhood Cancer study 9 (UKCCS), the UK Medical Research Council (MRC) ALL 97 (99) trial and from the Northern Institute of Cancer Research (NICR).…”

Section: Subjects and Methods Subjectsmentioning

confidence: 99%

“…4,6 Artefactual differences in allele frequencies between cases and controls can contribute to the estimation of spurious genetic variation; therefore, for the current analysis we imposed a number of additional quality control measures to the data set as advocated by Lee et al 8 when estimating heritability. Using PLINK software 12 we excluded SNPs in cases and controls that had a minor allele frequency (MAF)o0.01 or a Hardy-Weinberg equilibrium test with Po0.05.…”

Section: Quality Control Of Snp Genotypingmentioning

confidence: 99%

“…[4][5][6] These studies have robustly shown that singlenucleotide polymorphisms (SNPs) annotating the IKZF1 (7p12.2), CDKN2A (9p21.3), ARID5B (10q21.2) and CEBPE (14q11.2) genes influence disease risk (that is, P-values for associations o5.0 Â 10 À 8 ). [4][5][6] While each SNP only has a modest effect on an individual developing ALL, relative risks are among the strongest cancer associations identified by GWAS. 7 This is compatible with a scenario in which the inherited susceptibility to this malignancy has a strong polygenic basis.…”

Section: Introductionmentioning

confidence: 99%

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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: 94%

Section: Subjects and Methods Subjectsmentioning

confidence: 99%

Section: Quality Control Of Snp Genotypingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…In addition to major chromosomal aberrations, single nucleotide polymorphisms (SNP) were shown to be associated with the development of ALL. For example, SNPs in the genes ARID5B and CEBPE were found to be significantly related to ALL [6]. In addition to structural changes in the genome, epigenetic mechanisms are also important for ALL.…”

Section: Types and Progression Pathways Of Leukemiamentioning

confidence: 99%

Role of autophagy in the progression and suppression of leukemias

Ekiz

Can

Baran

2012

Critical Reviews in Oncology/Hematology

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Autophagy is a physiological process in which cellular components are degraded by the lysosomal machinery. Thereby, organelles are recycled and monomers are produced in order to maintain energy production. Current studies indicate autophagy might suppress or augment survival of cancer cells. Therefore, by elucidating the role of autophagy in cancer pathogenesis, novel therapeutic intervention points may be revealed. Leukemia therapy has advanced in recent years; but a definitive cure is still lacking. Since autophagy often is deregulated in this particular type of cancer, it is clear that future findings will have clinical implications. This review will discuss the current knowledge of autophagy in blood cancers. © 2011 Elsevier Ireland Ltd

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Role of Polymorphisms in Cancer Susceptibility

Tan

Ngeow

Tan

2010

Encyclopedia of Life Sciences

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Genetic variations or polymorphisms existing in the human genome can confer genetic susceptibility to cancer. Rare early onset cancer predisposition syndromes such as Li‐Fraumeni and Cowden syndromes typically involve germline mutations exhibiting high‐penetrance effects, but these account for only a small proportion of human cancers. For sporadic cancers, early monogenic association studies focusing on candidate genes with strong biological hypothesis have demonstrated an increased risk of cancers associated with polymorphisms in genes involved in cell cycle control, carcinogen metabolism, DNA ( deoxyribonucleic acid ) repair, apoptosis, inflammation and epigenetic regulation. Recent genome‐wide association studies have gone beyond the monogenic candidate gene approach to search across the entire genome for cancer susceptibility loci. This exponential knowledge has increased our understanding of carcinogenesis and provided translational research opportunities into personalised risk assessment, therapy and drug discovery. Key Concepts: Rare hereditary cancer syndromes such as Li‐Fraumeni syndrome typically involve high‐penetrance mutations of oncogenes or tumour suppressor genes, but account for a minority of human cancers. The overwhelming majority of cancer susceptibility in the normal population is likely attributable to common genetic variations or polymorphisms in the human genome. Candidate gene approaches have identified several polymorphisms of known oncogenes and tumour suppressor genes, as well as genes involved in carcinogen metabolism, DNA repair and cell‐cycle control that are associated with cancer susceptibility. The increased risk conferred by each polymorphism is small. Data from separate association studies are often conflicting. Meta‐analysis can be used to integrate conflicting findings across several studies. The functional mechanisms by which many polymorphisms lead to cancer susceptibility has not been established. In recent years, high‐resolution public databases of genetic information, technological advances and reduced costs of genotyping have led to a rapid emergence of genome‐wide association studies (GWAS) that survey the entire genome for cancer susceptibility loci. By these approaches, putative risk loci, novel cancer genes have increased biological insights into carcinogenesis. This exponential increase in knowledge has opened new horizons to understand oncogenesis and translational research opportunities into personalised risk assessment, therapy and drug discovery.

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Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia

Cited by 431 publications

References 22 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

Role of autophagy in the progression and suppression of leukemias

Role of Polymorphisms in Cancer Susceptibility

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