Julie Dubois1, Gabriel Etienne2, Audrey Laroche-Clary3, Axelle Lascaux4, Audrey Bidet4, Eric Lippert5, Sofiane Ait-ouferoukh3, Veronique Saada6, Jean-Baptiste Micol6, Krimo Bouabdallah4, Jacques Robert7. 1. INSERM U916, Bordeaux, France; Department of Medical Biology, Institut Bergonié, Bordeaux, France. Electronic address: j.dubois@bordeaux.unicancer.fr. 2. Department of Hematology, Institut Bergonié, Bordeaux, France. 3. INSERM U916, Bordeaux, France. 4. Department of Hematology, Hôpital du Haut-Lévêque, CHU de Bordeaux, Pessac, France. 5. Department of Hematology, Hôpital du Haut-Lévêque, CHU de Bordeaux, Pessac, France; Université Bordeaux Segalen, Bordeaux, France. 6. Department of Hematology, Institut Gustave-Roussy, Villejuif, France. 7. INSERM U916, Bordeaux, France; Department of Medical Biology, Institut Bergonié, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.
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.
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 MDSpatients (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.