title: A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.
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.
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. kyle.walsh@ucsf.edu.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Smirnov
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Semira
authors.initials: S
authors.lastname: Gonseth
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Alyson A
authors.initials: AA
authors.lastname: Endicott
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Jianqiao
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Terri
authors.initials: T
authors.lastname: Rice
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Cecilia H
authors.initials: CH
authors.lastname: Fu
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Lucie S
authors.initials: LS
authors.lastname: McCoy
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lachance
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.affiliation: Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ma
authors.affiliation: School of Public Health, University of California Berkeley, Berkeley, California.
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D016022:Case-Control Studies; D002648:Child; D019143:Evolution, Molecular; D005260:Female; D019942:Genes, p16; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*