Identification of methylguanine methyltransferase polymorphisms as genetic markers of individual susceptibility to therapy-related myeloid neoplasms

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Abstract

Purpose Myelodysplastic syndromes (MDS) are pre-leukaemic haematopoietic stem cell disorders. Among them, 10-20% occur after chemotherapy and/or radiotherapy, and are called 'therapy-related MDS' (t-MDS). The aim of this study was to identify genetic markers in t-MDS. Methods A prospective cohort of 59 MDS patients (39 de novo MDS, 20 t-MDS) was studied. A total of 384 single nucleotide polymorphisms (SNP) selected among genes involved in DNA repair, drug metabolism and transport, signal transduction and oncogenesis, were genotyped using a custom-made SNP chip. Results Two non-synonymous SNPs present in the methylguanine methyltransferase (MGMT) gene, in complete linkage disequilibrium, were significantly associated with t-MDS: rs2308321 and rs2308327, with a raw p value of 7.4 × 10-5 and a corrected p value after Benjamini-Hochberg correction of 0.014. Other associations tested between clinical and cytogenetic features and SNP chip gene variants gave corrected p values above 0.05. A validation cohort was separately constituted of 43 patients (24 de novo MDS, 19 t-MDS) and the two MGMT SNPs were genotyped; it confirmed a significant association between the variant allele of MGMT and t-MDS (p = 0.038). Conclusion We thus identified a putative marker of the risk to develop MDS after cancer treatment. © 2013 Elsevier Ltd. All rights reserved.

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Dubois, J., Etienne, G., Laroche-Clary, A., Lascaux, A., Bidet, A., Lippert, E., … Robert, J. (2014). Identification of methylguanine methyltransferase polymorphisms as genetic markers of individual susceptibility to therapy-related myeloid neoplasms. European Journal of Cancer, 50(2), 418–424. https://doi.org/10.1016/j.ejca.2013.10.012

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