An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia.
Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying adult patients at high-risk. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by National Cancer Institute (NCI) criteria. CEP72 promoter genotype (rs924607) was determined using polymerase chain reaction (PCR)-based single nucleotide polymorphism (SNP) genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs. 10%, P = 0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (P = 0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy.
Section of Hematology Oncology, University of Chicago Medicine and Comprehensive Cancer Center, Chicago, Illinois, USA.|Alliance for Clinical Trials in Oncology, Chicago, Illinois, USA.
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Stock
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Diouf
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Crews
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Pei
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Cheng
Alliance for Clinical Trials in Oncology, Chicago, Illinois, USA.|Alliance Statistics and Data Center; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
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Laumann
Alliance for Clinical Trials in Oncology, Chicago, Illinois, USA.|Alliance Statistics and Data Center; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
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Mandrekar
University of Pennsylvania, ECOG-ACRIN Cancer Research Group, Philadelphia, Pennsylvania, USA.
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Luger
Cleveland Clinic, Southwest Oncology Cooperative Group, Cleveland, Ohio, USA.
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Advani
Alliance for Clinical Trials in Oncology, Chicago, Illinois, USA.
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Stone
Section of Hematology Oncology, University of Chicago Medicine and Comprehensive Cancer Center, Chicago, Illinois, USA.|Alliance for Clinical Trials in Oncology, Chicago, Illinois, USA.
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Larson
Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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Evans
D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D014750:Vincristine / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
C542475:CEP72 protein, human; D008869:Microtubule-Associated Proteins; D014750:Vincristine