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.

• Authors: Julie Dubois, Gabriel Etienne, Audrey Laroche-Clary, Axelle Lascaux, Audrey Bidet, Eric Lippert, Sofiane Ait-ouferoukh, Veronique Saada, Jean-Baptiste Micol, Krimo Bouabdallah, Jacques Robert
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 50 Issue 2 Pg. 418-24 (Jan 2014) ISSN: 1879-0852 [Electronic] England
• PMID: 24238921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• O(6)-Methylguanine-DNA Methyltransferase

Topics

• Adult
• Aged
• Aged, 80 and over
• Chemoradiotherapy (adverse effects)
• Female
• Gene Frequency
• Genetic Predisposition to Disease (genetics)
• Genotype
• Humans
• Linkage Disequilibrium
• Male
• Middle Aged
• Myelodysplastic Syndromes (etiology, genetics)
• Neoplasms (therapy)
• O(6)-Methylguanine-DNA Methyltransferase (genetics)
• Polymorphism, Single Nucleotide
• Prospective Studies
• Risk Factors