Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia

被引：22

作者：

Karol, S. E. ^{[1
,2
]}

Larsen, E. ^{[3
]}

Cheng, C. ^{[4
]}

Cao, X. ^{[4
]}

Yang, W. ^{[5
]}

Ramsey, L. B. ^{[6
]}

Fernandez, C. A. ^{[7
]}

McCorkle, J. R. ^{[5
]}

Paugh, S. W. ^{[5
]}

Autry, R. J. ^{[5
]}

Lopez-Lopez, E. ^{[5
]}

Diouf, B. ^{[5
]}

Jeha, S. ^{[2
]}

Pui, C-H ^{[2
]}

Raetz, E. A. ^{[8
]}

Winick, N. J. ^{[9
]}

Carroll, W. L. ^{[10
]}

Hunger, S. P. ^{[11
]}

Loh, M. L. ^{[12
]}

Devidas, M. ^{[13
,14
]}

Evans, W. E. ^{[5
]}

Yang, J. J. ^{[5
]}

Relling, M. V. ^{[5
]}

机构：

[1] St Jude Childrens Res Hosp, Comprehens Canc Ctr, 332 N Lauderdale St, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] Maine Med Ctr, Dept Pediat, Portland, ME 04102 USA

[4] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 262 Danny Thomas Pl,Room I-5112, Memphis, TN 38105 USA

[6] Cincinnati Childrens Hosp Med Ctr, Dept Pharm Res, Cincinnati, OH 45229 USA

[7] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA

[8] Univ Utah, Dept Pediat, Salt Lake City, UT USA

[9] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA

[10] NYU, Langone Med Ctr, Dept Pediat & Pathol, Perlmutter Canc Ctr, New York, NY USA

[11] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[12] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA USA

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

[14] Univ Florida, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA

来源：

LEUKEMIA | 2017年 / 31卷 / 06期

基金：

美国国家卫生研究院;

关键词：

MINIMAL RESIDUAL DISEASE; GENOME-WIDE ASSOCIATION; INTENSIVE CHEMOTHERAPY; YOUNG-ADULTS; LUNG-CANCER; CHILDREN; SURVIVAL; POLYMORPHISMS; ASPARAGINASE; ADOLESCENTS;

D O I：

10.1038/leu.2017.24

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR) = 2.32, P = 2.27 x 10(-4), model with SNPs HR = 1.07, P = 0.79; for Hispanics: model without SNPs HR = 1.7, P = 8.23 x 10(-5), model with SNPs HR = 1.31, P = 0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P = 0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

引用

页码：1325 / 1332

页数：8

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