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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.

Publication ,  Journal Article
Walsh, KM; de Smith, AJ; Hansen, HM; Smirnov, IV; Gonseth, S; Endicott, AA; Xiao, J; Rice, T; Fu, CH; McCoy, LS; Lachance, DH; Wiencke, JK ...
Published in: Cancer Res
November 15, 2015

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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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 15, 2015

Volume

75

Issue

22

Start / End Page

4884 / 4894

Location

United States

Related Subject Headings

  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Male
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genes, p16
  • Female
 

Citation

APA
Chicago
ICMJE
MLA
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Walsh, K. M., de Smith, A. J., Hansen, H. M., Smirnov, I. V., Gonseth, S., Endicott, A. A., … Wiemels, J. L. (2015). A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. Cancer Res, 75(22), 4884–4894. https://doi.org/10.1158/0008-5472.CAN-15-1105
Walsh, Kyle M., Adam J. de Smith, Helen M. Hansen, Ivan V. Smirnov, Semira Gonseth, Alyson A. Endicott, Jianqiao Xiao, et al. “A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.Cancer Res 75, no. 22 (November 15, 2015): 4884–94. https://doi.org/10.1158/0008-5472.CAN-15-1105.
Walsh KM, de Smith AJ, Hansen HM, Smirnov IV, Gonseth S, Endicott AA, et al. A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. Cancer Res. 2015 Nov 15;75(22):4884–94.
Walsh, Kyle M., et al. “A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.Cancer Res, vol. 75, no. 22, Nov. 2015, pp. 4884–94. Pubmed, doi:10.1158/0008-5472.CAN-15-1105.
Walsh KM, de Smith AJ, Hansen HM, Smirnov IV, Gonseth S, Endicott AA, Xiao J, Rice T, Fu CH, McCoy LS, Lachance DH, Eckel-Passow JE, Wiencke JK, Jenkins RB, Wrensch MR, Ma X, Metayer C, Wiemels JL. A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution. Cancer Res. 2015 Nov 15;75(22):4884–4894.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 15, 2015

Volume

75

Issue

22

Start / End Page

4884 / 4894

Location

United States

Related Subject Headings

  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Male
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genes, p16
  • Female