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


CONCLUSIONS
We thus identified a putative marker of the risk to develop MDS after cancer treatment.
INSERM U916, Bordeaux, France; Department of Medical Biology, Institut Bergonié, Bordeaux, France. Electronic address: j.dubois@bordeaux.unicancer.fr.
Julie
J
Dubois
Department of Hematology, Institut Bergonié, Bordeaux, France.
Gabriel
G
Etienne
INSERM U916, Bordeaux, France.
Audrey
A
Laroche-Clary
Department of Hematology, Hôpital du Haut-Lévêque, CHU de Bordeaux, Pessac, France.
Axelle
A
Lascaux
Department of Hematology, Hôpital du Haut-Lévêque, CHU de Bordeaux, Pessac, France.
Audrey
A
Bidet
Department of Hematology, Hôpital du Haut-Lévêque, CHU de Bordeaux, Pessac, France; Université Bordeaux Segalen, Bordeaux, France.
Eric
E
Lippert
INSERM U916, Bordeaux, France.
Sofiane
S
Ait-ouferoukh
Department of Hematology, Institut Gustave-Roussy, Villejuif, France.
Veronique
V
Saada
Department of Hematology, Institut Gustave-Roussy, Villejuif, France.
Jean-Baptiste
JB
Micol
Department of Hematology, Hôpital du Haut-Lévêque, CHU de Bordeaux, Pessac, France.
Krimo
K
Bouabdallah
INSERM U916, Bordeaux, France; Department of Medical Biology, Institut Bergonié, Bordeaux, France; Université Bordeaux Segalen, Bordeaux, France.
Jacques
J
Robert
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059248:Chemoradiotherapy / Q000009:adverse effects; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics*; D009369:Neoplasms / Q000628:therapy; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors
D019853:O(6)-Methylguanine-DNA Methyltransferase
Gene polymorphisms; Methylguanine methyltransferase; Therapy-related myelodysplastic syndromes