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A heritable missense polymorphism in CDKN2A confers strong risk of childhood acute lymphoblastic leukemia and is preferentially selected during clonal evolution
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Details:
  • Pubmed ID:
    26527286
  • Pubmed Central ID:
    PMC4651745
  • Description:
    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.

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  • Funding:
    R01CA155461/CA/NCI NIH HHS/United States
    R21 CA158568/CA/NCI NIH HHS/United States
    P50 CA108961/CA/NCI NIH HHS/United States
    R01 CA133996/CA/NCI NIH HHS/United States
    P50 CA097007/CA/NCI NIH HHS/United States
    HHSN261201000035/CA/NCI NIH HHS/United States
    RC1 NS068222/NS/NINDS NIH HHS/United States
    R01 CA142665/CA/NCI NIH HHS/United States
    R25 CA112355/CA/NCI NIH HHS/United States
    R01 ES011740/ES/NIEHS NIH HHS/United States
    R37 CA036401/CA/NCI NIH HHS/United States
    U24 CA114766/CA/NCI NIH HHS/United States
    RC4 CA156449/CA/NCI NIH HHS/United States
    HHSN261201000034/CA/NCI NIH HHS/United States
    R01 CA140729/CA/NCI NIH HHS/United States
    P50 CA097257/CA/NCI NIH HHS/United States
    P30 CA021765/CA/NCI NIH HHS/United States
    R01 CA155461/CA/NCI NIH HHS/United States
    R25CA112355/CA/NCI NIH HHS/United States
    P01ES018172/ES/NIEHS NIH HHS/United States
    P01 ES018172/ES/NIEHS NIH HHS/United States
    P30 CA015083/CA/NCI NIH HHS/United States
    U10 CA098543/CA/NCI NIH HHS/United States
    R01ES09137/ES/NIEHS NIH HHS/United States
    U58 DP003862/DP/NCCDPHP CDC HHS/United States
    R01 CA036401/CA/NCI NIH HHS/United States
    R01 ES009137/ES/NIEHS NIH HHS/United States
    HHSN261201000140/CA/NCI NIH HHS/United States
    HHSN261201000035/PC,CA/None/None
    P50 CA093459/CA/NCI NIH HHS/United States
    U01 GM092666/GM/NIGMS NIH HHS/United States
    R01 CA052689/CA/NCI NIH HHS/United States
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