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

被引：82

作者：

Perez-Andreu, Virginia ^{[1
]}

Roberts, Kathryn G. ^{[2
]}

Xu, Heng ^{[1
,3
,4
]}

Smith, Colton ^{[1
]}

Zhang, Hui ^{[1
]}

Yang, Wenjian ^{[1
]}

Harvey, Richard C. ^{[5
]}

Payne-Turner, Debbie ^{[2
]}

Devidas, Meenakshi ^{[6
,7
,8
]}

Cheng, I-Ming ^{[9
]}

Carroll, William L. ^{[10
]}

Heerema, Nyla A. ^{[11
]}

Carroll, Andrew J. ^{[12
]}

Raetz, Elizabeth A. ^{[13
]}

Gastier-Foster, Julie M. ^{[14
]}

Marcucci, Guido ^{[15
]}

Bloomfield, Clara D. ^{[15
]}

Mrozek, Krzysztof ^{[15
]}

Kohlschmidt, Jessica ^{[15
,16
,17
]}

Stock, Wendy ^{[18
]}

Kornblau, Steven M. ^{[19
]}

Konopleva, Marina ^{[20
]}

Paietta, Elisabeth ^{[21
]}

Rowe, Jacob M. ^{[22
]}

Luger, Selina M. ^{[23
]}

Tallman, Martin S. ^{[24
]}

Dean, Michael ^{[25
]}

Burchard, Esteban G. ^{[26
,27
]}

Torgerson, Dara G. ^{[26
,27
]}

Yue, Feng ^{[28
]}

Wang, Yanli ^{[28
]}

Pui, Ching-Hon ^{[29
]}

Jeha, Sima ^{[29
]}

Relling, Mary V. ^{[1
]}

Evans, William E. ^{[1
]}

Gerhard, Daniela S. ^{[30
]}

Loh, Mignon L. ^{[31
,32
]}

Willman, Cheryl L. ^{[9
]}

Hunger, Stephen P. ^{[33
,34
]}

Mullighan, Charles G. ^{[2
]}

Yang, Jun J. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[3] Sichuan Univ, West China Med Sch, State Key Lab Biotherapy, Chengdu 610064, Peoples R China

[4] Sichuan Univ, West China Med Sch, Ctr Canc, Chengdu 610064, Peoples R China

[5] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA

[6] Univ Florida, Coll Med, Dept Biostat, Gainesville, FL USA

[7] Univ Florida, Dept Biostat, Coll Publ Hlth, Gainesville, FL USA

[8] Univ Florida, Coll Hlth Profess, Dept Biostat, Gainesville, FL USA

[9] Univ New Mexico, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA

[10] NYU, Laura & Isaac Perlmutter Canc Ctr, Langone Med Ctr, New York, NY USA

[11] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA

[12] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA

[13] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[14] Ohio State Univ, Nationwide Childrens Hosp, Columbus, OH 43210 USA

[15] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

[16] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA

[17] Mayo Clin, Ctr Data, Rochester, MN USA

[18] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA

[19] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Sect Mol Hematol & Therapy, Houston, TX 77030 USA

[20] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[21] Yeshiva Univ, Albert Einstein Coll Med, Dept Med Oncol, New York, NY 10033 USA

[22] Rambam Med Ctr, Haifa, Israel

[23] Univ Penn, Hematol Malignancies Program, Div Hematol Oncol, Philadelphia, PA 19104 USA

[24] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA

[25] NCI, Expt Immunol Lab, Frederick, MD 21701 USA

[26] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[27] Univ Calif San Francisco, Dept Med, San Francisco, CA USA

[28] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA USA

[29] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA

[30] NCI, Off Canc Genom, Bethesda, MD 20892 USA

[31] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA

[32] Univ Calif San Francisco, Helen Diller Family Canc Ctr, San Francisco, CA 94143 USA

[33] Univ Colorado, Sch Med, Aurora, CO USA

[34] Univ Colorado, Sch Med, Childrens Hosp, Aurora, CO USA

来源：

BLOOD | 2015年 / 125卷 / 04期

基金：

美国国家卫生研究院;

关键词：

HYPER-CVAD; VARIANTS; RISK; CANCER; DIAGNOSIS; CHILDREN; RELAPSE; REGIMEN; KINASE; LOCI;

D O I：

10.1182/blood-2014-09-595744

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 x 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 x 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 x 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 x 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.

引用

页码：680 / 686

页数：7

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