Risk of acute promyelocytic leukemia in multiple sclerosis: Coding variants of DNA repair genes

S. K. Hasan, F. Buttari, T. Ottone, M. T. Voso, S. Hohaus, E. Marasco, V. Mantovani, P. Garagnani, M. A. Sanz, L. Cicconi, G. Bernardi, D. Centonze, F. Lo-Coco

Research output: Contribution to journalArticle

Abstract

Background: Single nucleotide polymorphisms (SNPs) in double-strand break repair genes may alter DNA repair capacity and, in turn, confer predisposition to leukemia. We analyzed polymorphic variants of DNA repair and detoxification genes in patients with multiple sclerosis (MS) who developed secondary acute promyelocytic leukemia (sAPL), in most cases after treatment with mitoxantrone (MTZ). Methods: Using MassARRAY high-throughput DNA analysis with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we genotyped patients with sAPL (n = 20) developed after treatment of MS (18 out 20 treated with MTZ) for the presence of 210 SNPs of 22 genes mostly involved in DNA repair and drug detoxification. Patients with MS who did not develop sAPL including 41 treated with MTZ (n = 253 and 41, respectively) and healthy blood donors (n = 310) were also genotyped as controls. Results: We observed risk allele frequency between MS and sAPL for BRCA2 (rs1801406): 6% and 26%, p = 0.007; XRCC5 (rs207906): 2.5% and 15%, p = 0.016; CYP3A4 (rs2740574): 4.5% and 25%, p = 0.0035. The association of homozygous variants of BRCA2 and XRCC5 yielded higher risk of sAPL (MS vs sAPL: 0.4% and 18%, p = 0.001). We also observed a significant association between a SNP in the promoter region (rs2740574) of CYP3A4, an enzyme involved in the metabolism of chemotherapeutic agents and development of sAPL. Conclusions: Increased susceptibility to develop sAPL in patients with MS receiving MTZ may be linked to genetic variants in DNA repair and drug-metabolizing enzymes that result in impaired detoxification of chemotherapy or inefficient repair of drug-induced genetic damage.

Original languageEnglish
Pages (from-to)1059-1065
Number of pages7
JournalNeurology
Volume76
Issue number12
DOIs
Publication statusPublished - Mar 22 2011

ASJC Scopus subject areas

  • Clinical Neurology

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    Hasan, S. K., Buttari, F., Ottone, T., Voso, M. T., Hohaus, S., Marasco, E., Mantovani, V., Garagnani, P., Sanz, M. A., Cicconi, L., Bernardi, G., Centonze, D., & Lo-Coco, F. (2011). Risk of acute promyelocytic leukemia in multiple sclerosis: Coding variants of DNA repair genes. Neurology, 76(12), 1059-1065. https://doi.org/10.1212/WNL.0b013e318211c3c8