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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.

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.

SUBMITTER: Walsh KM

PROVIDER: S-EPMC4651745 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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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.

Walsh Kyle M KM de Smith Adam J AJ Hansen Helen M HM Smirnov Ivan V IV Gonseth Semira S Endicott Alyson A AA Xiao Jianqiao J Rice Terri T Fu Cecilia H CH McCoy Lucie S LS Lachance Daniel H DH Eckel-Passow Jeanette E JE Wiencke John K JK Jenkins Robert B RB Wrensch Margaret R MR Ma Xiaomei X Metayer Catherine C Wiemels Joseph L JL

Cancer research 20151102 22

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 9p2 ...[more]

PMID: 26527286

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Project description:BACKGROUND:It has been shown that approximately half of survivors of childhood acute lymphoblastic leukemia (ALL) have symptomatic late effects (LE) that may be severe or life-threatening. The aim of our study was to assess the health status of childhood ALL survivors after over 10 years of follow-up and to assess its relationships with gene polymorphisms, numbers and types of LEs, as well as with intensity of chemotherapy and cranial radiotherapy (CRT). METHODS:We conducted a telephone survey in 125 ALL survivors (median time from completion of treatment was 12 years) and compared the results with those obtained in our previous study. Most of the patients were followed-up by local providers. RESULTS:The prevalence of LEs of approximately 50% was similar in both study groups. More than one LE was found in almost 25% of patients. Endocrine LEs were less frequent than in our previous study (44% vs 22%), probably due to underdiagnosis. The prevalence of hepatitis B/C decreased from 30%/50 to 18% (counted together), and prevalence of neurologic LEs decreased from 18 to 6%. The increase in the rate of second malignancies was not significant (2% vs. 3%). Sixty four percent of patients continued their education at the time of the study. Approximately 51% of ALL survivors who have completed their education by the time of the study had no permanent employment, including 4 mothers of infants and 3 persons qualified for a disability living allowance. These employment problems may have been due to cognitive impairment. The offspring of the ALL survivors included 11 children, all of them healthy. Further analysis showed higher prevalence of hepatitis in patients treated with CRT (p?=?0.0001). Genetic studies revealed higher prevalence of hepatitis in patients homozygous for the rs9939609A variant of the FTO gene compared with other patients (p?=?0.03). Moreover, wild-type rs1137101 polymorphism (Q223R) of the and leptin receptor gene was more frequent in patients with psychological LEs (p?=?0.03). CONCLUSIONS:The prevalence of LEs in ALL survivors is of key importance. The transition of childhood ALL survivors from pediatric to adult care should be urgently improved to maintain continued follow-up provide high-quality care. TRIAL REGISTRATION:Bioethics Committee of the Jagiellonian University approved the study protocol. Registration number: KBET/113/B/2006.

Dataset Information

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.

Publications

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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