Identification Of MGMT Polymorphisms As Genetic Markers Of Individual Susceptibility To Therapy-Related Myeloid Neoplasms

Myelodysplastic syndromes (MDS) are pre-leukemic hematopoietic stem cell disorders. Among them, 10 to 20% occur after cytotoxic treatment for prior cancer by chemotherapy and/or radiotherapy, and are called “therapy-related MDS” (t-MDS). However, only a minimal proportion of patients exposed to anticancer drugs or radiation develop secondary MDS, suggesting that a genetic component takes place in individual susceptibility. Genetic determinants of susceptibility to t-MDS are unknown. The aim of this study was to identify such genetic markers.

A prospective cohort of 59 MDS patients (39 de novo MDS, 20 t-MDS) was studied. Using a custom-made SNP chip, we genotyped a total of 384 single nucleotide polymorphisms (SNP) selected among genes involved in DNA repair, drug metabolism and transport, signal transduction and oncogenesis. We analysed the associations existing between each genotype and several clinical and pathological features (therapy-related character, adverse cytogenetic findings, IPSS score, acute leukaemia stage), using Benjamini-Hochberg correction for multiple testing.

Two non-synonymous SNPs present in the methylguanine methyltransferase (MGMT) gene and 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 of 0.014. Other associations tested between clinical and cytogenetic features and SNP chip gene variants were not significant. An independent validation cohort was separately constituted of 43 patients (24 de novo MDS, 19 t-MDS) and the two MGMT SNPs were genotyped by pyrosequencing; this allowed us to confirm a significant association between the variant allele of MGMT and the therapy-related character of MDS (p=0.038).

MGMT encodes a protein involved in direct DNA repair by removing alkyl adducts from guanine at oxygen-6 position. The two SNPs identified both induce a change in amino acid sequence of the protein (rs2308321: Ile143Val, rs2308327: Lys178Arg) and may therefore impact the functional capacity of the enzyme. A reduced activity of MGMT variant protein as compared to wild-type would explain an increased sensitivity to alkylating agents and a higher risk for secondary tumour development. Nevertheless, the impact of MGMT variants on protein expression and activity was not demonstrated in functional studies conducted previously.

This gene-oriented susceptibility study allowed to detect, in both an identification and a validation cohort, a significant association between a variant allele of the DNA repair gene MGMT and the therapy-related character of MDS. We thus identified a putative marker of the risk to develop MDS after cancer treatment. This observation may lead to special consideration of the patients at risk when they are prescribed chemotherapy or radiotherapy and to the choice of treatment regimen producing minimal DNA damage.

Etienne:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.