Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults

Virginia Perez-Andreu, Kathryn G. Roberts, Heng Xu, Colton Smith, Hui Zhang, Wenjian Yang, Richard C. Harvey, Debbie Payne-Turner, Meenakshi Devidas, I. Ming Cheng, William L. Carroll, Nyla A. Heerema, Andrew J. Carroll, Elizabeth A. Raetz, Julie M. Gastier-Foster, Guido Marcucci, Clara D. Bloomfield, Krzysztof Mrózek, Jessica Kohlschmidt, Wendy StockSteven M. Kornblau, Marina Konopleva, Elisabeth Paietta, Jacob M. Rowe, Selina M. Luger, Martin S. Tallman, Michael Dean, Esteban G. Burchard, Dara G. Torgerson, Feng Yue, Yanli Wang, Ching Hon Pui, Sima Jeha, Mary V. Relling, William E. Evans, Daniela S. Gerhard, Mignon L. Loh, Cheryl L. Willman, Stephen P. Hunger, Charles G. Mullighan, Jun J. Yang

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms(SNPs) in 308AYAALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10-8 in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10-10) and rs3781093, OR, 1.73 (P = 3.2 × 10-9). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10-11). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

Original languageEnglish (US)
Pages (from-to)680-686
Number of pages7
JournalBlood
Volume125
Issue number4
DOIs
StatePublished - Jan 22 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Perez-Andreu, V., Roberts, K. G., Xu, H., Smith, C., Zhang, H., Yang, W., Harvey, R. C., Payne-Turner, D., Devidas, M., Cheng, I. M., Carroll, W. L., Heerema, N. A., Carroll, A. J., Raetz, E. A., Gastier-Foster, J. M., Marcucci, G., Bloomfield, C. D., Mrózek, K., Kohlschmidt, J., ... Yang, J. J. (2015). Lymphoid neoplasia: A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults. Blood, 125(4), 680-686. https://doi.org/10.1182/blood-2014-09-595744