TY - JOUR
T1 - A heritable missense polymorphism in CDKN2A confers strong risk of childhood acute lymphoblastic leukemia and is preferentially selected during clonal evolution
AU - Walsh, Kyle M.
AU - De Smith, Adam J.
AU - Hansen, Helen M.
AU - Smirnov, Ivan V.
AU - Gonseth, Semira
AU - Endicott, Alyson A.
AU - Xiao, Jianqiao
AU - Rice, Terri
AU - Fu, Cecilia H.
AU - McCoy, Lucie S.
AU - Lachance, Daniel H.
AU - Eckel-Passow, Jeanette E.
AU - Wiencke, John K.
AU - Jenkins, Robert B.
AU - Wrensch, Margaret R.
AU - Ma, Xiaomei
AU - Metayer, Catherine
AU - Wiemels, Joseph L.
N1 - Funding Information:
This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Melanoma case-control data were obtained from dbGaP Study Accession phs000187.v1.p1 (High Density SNP Association Analysis of Melanoma: Case-Control and Outcomes Investigation) Pancreatic cancer case-control data were obtained from dbGaP Study Accession phs000206.v4.p3 (CGEMS Pancreatic Cancer (PanScan)). The ALL Relapse GWAS dataset used for the analyses described in this article were obtained from dbGaP study accession phs000638.v1.p1 (Genome-Wide Association Study of Relapse of Childhood Acute Lymphoblastic Leukemia). The authors thank the clinical investigators at the following collaborating hospitals for help in recruiting patients: University of California Davis Medical Center (Dr. Jonathan Ducore), University of California San Francisco (Drs. Mignon Loh and Katherine Matthay), Children''s Hospital of Central California (Dr. Vonda Crouse), Lucile Packard Children''s Hospital (Dr. Gary Dahl), Children''s Hospital Oakland (Dr. James Feusner), Kaiser Permanente Roseville (formerly Sacramento) (Drs. Kent Jolly and Vincent Kiley), Kaiser Permanente Santa Clara (Drs. Carolyn Russo, Alan Wong, and Denah Taggart), Kaiser Permanente San Francisco (Dr. Kenneth Leung), and Kaiser Permanente Oakland (Drs. Daniel Kronish and Stacy Month). Bioinformatic analysis of NGS data from glioma cases and controls was performed with extensive support from Yuanyuan Xiao. Paige M. Bracci contributed helpful analytic advice for calculating agreement between MLPA and ddPCR assays via Bland-Altman plots. This work was financially supported by NCI R01CA155461 (J.L. Wiemels, X. Ma), NCI R25CA112355 (K.M. Walsh), NIEHS and EPA P01ES018172 (C. Metayer, J.L. Wiemels), NIEHS R01ES09137 (C. Metayer, J.L. Wiemels), and grants from the Swiss Cancer League and the SICPA Foundation (S. Gonseth). Work at The University of California, San Francisco Department of Neurological Surgery was supported by the NIH (grant numbers R01CA52689 and P50CA097257), as well as the National Brain Tumor Foundation, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research, the Robert Magnin Newman Endowed Chair in Neuro-oncology, and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper, andWilliam Martinusen. Work at the Mayo Clinic was supported by the NIH (grant numbers P50CA108961 andP30 CA15083), the National Institute of Neurological Disorders and Stroke (grant number RC1NS068222Z), the Bernie and Edith Waterman Foundation, and the Ting Tsung and Wei Fong Chao Family Foundation. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. Research support to collect data and develop an application to support the "high Density SNP Association Analysis of Melanoma" was provided by 3P50CA093459, 5P50CA097007, 5R01ES011740, and 5R01CA133996. The ALL Relapse GWAS dataset was generated at St. Jude Children''s ResearchHospital and by the Children''s Oncology Group, supporte by NIH grants CA142665, CA21765, CA158568, CA156449, CA36401, CA98543, CA114766, CA140729, and U01GM92666, Jeffrey Pride Foundation, the National Childhood Cancer Foundation, and by ALSAC. The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute''s Surveillance, Epidemiology and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention''s National Program of Cancer Registries, under agreement # U58DP003862-01 awarded to the California Department of Public Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/11/15
Y1 - 2015/11/15
N2 - 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.
AB - 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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U2 - 10.1158/0008-5472.CAN-15-1105
DO - 10.1158/0008-5472.CAN-15-1105
M3 - Article
C2 - 26527286
AN - SCOPUS:84955275619
VL - 75
SP - 4884
EP - 4894
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 22
ER -