A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution
Year: 2015
Type: article
Study design: Observational Study
Abstract: Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case-control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10(-9)) and Hispanic children (OR, 2.77; P = 3.78 × 10(-4)). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS "hits" and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors.
Source: Cancer Research
Authors: Kyle M. Walsh, Adam J. de Smith, Helen M. Hansen, Ivan V. Smirnov, Semira Gonseth, Alyson A. Endicott, Jianqiao Xiao, Terri Rice, Cecilia H. Fu, Lucie S. McCoy, Daniel H. Lachance, Jeanette E. Eckel-Passow, John K. Wiencke, Robert B. Jenkins, Margaret R. Wrensch, Xiaomei Ma, Catherine Metayer, Joseph L. Wiemels
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Environmental and Molecular Epidemiology of Childhood Leukemia, Identification of 9p and 20q Germline Alterations in Glioblastoma Pathogenesis, Genome-Wide Association Study of Childhood Leukemia by Hispanic Status, Drug resistant pathways in relapsed acute lymphoblastic leukemia (ALL), PAAR4Kids-Pharmacogenomics of Anticancer Agents Research in Children, G2238803135, M D Anderson Cancer Center Head & Neck SPORE, Center for Integrative Research on Childhood Leukemia and the Environment, Glucocorticoids in Lymphoblastic Leukemia, Molecular Epidemiology of DNA Repair in Head and Neck Cancer, G3161224617, Statistical Methods for Gene Environment Interactions In Lung Cancer, Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), G480705112, G5333917095, G5570217171, PDE4B and pharmacoethnicity of childhood leukemia, Pharmacogenomics of Racial Disparities in Childhood Leukemia Outcomes, Mayo SPORE in Brain Cancer, Children's Oncology Group Chair's Grant, PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), Training in Molecular& Genetic Epidemiology of Cancer, Genetic and molecular epidemiology of adult glioma, Mayo Clinic Comprehensive Cancer Center Support Grant, Cancer Center Support Grant (CCSG), Brain Tumor SPORE Grant, The University of Texas M. D. Anderson Cancer Center SPORE in Melanoma
OpenAlex ID: W2230634176