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

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. [Copyright &y& Elsevier]