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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4151-4157.
Prepublished online as a Blood First Edition Paper on January 30, 2007; DOI 10.1182/blood-2006-10-054528.
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Submitted October 27, 2006
Accepted January 11, 2007
Ancestry and pharmacogenetics of antileukemic drug toxicity
Shinji Kishi, Cheng Cheng, Deborah French, Deqing Pei, Soma Das, Edwin H. Cook, Nobuko Hijiya, Carmelo Rizzari, Gary L. Rosner, Tony Frudakis, Ching-Hon Pui, William E. Evans, and Mary V. Relling*
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, United States
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, United States
Department of Psychiatry, Pediatrics, and Human Genetics, University of Chicago, Chicago, IL, United States
Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States
Clinica Pediatrica, Universita di Milano, Milano, Italy
Biostatistics, M. D. Anderson Cancer Center, Houston, TX, United States
DNAPrint Genomics, Sarasota, FL, United States
University of Tennessee, Memphis, TN, United States
Department of Hematologic Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, United States
* Corresponding author; email: mary.relling{at}stjude.org.
Treatment-related toxicity in acute lymphoblastic leukemia (ALL) cannot only be life-threatening but may affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex and disease risk group (lower vs. higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurological) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR] 6·85 [95% confidence interval 1·73-27·0]) and cytochrome P4503A5 (OR 4·61 [1·11-19·2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR 10·4 [1·35-80·4]) as it also did during continuation (OR 2·01 [1·06-4·11]). In all three treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (p = 0·017, < 0·0001, and < 0·0001, respectively) and methotrexate clearance (p = 0·028), which was also independently associated with hyperbilirubinemia (p = 0·026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germline polymorphisms are significant determinants of toxicity of antileukemic therapy.
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