An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia

Abstract

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.

Figure 1

(Panel A) Percentage of patients who developed grade 2-4 vincristine-induced neuropathy [left] and percentage of matched controls [right] who had the CEP72 T/T promoter genotype (at rs924607) [red bars] or the CEP72 C/C or C/T genotype (at rs924607) [blue bars].(Panel B) Percentage of patients who developed grade 2-4 vincristine-induced neuropathy [red bars] among patients with the CEP72 promoter C/C or C/T genotype (left) or with the CEP72 T/T promoter genotype at rs924607.