Polymorphisms of detoxification and DNA repair enzymes in myelodyplastic syndromes☆
Introduction
The integrity of DNA is under constant attack both from the inside and the outside of the cell. Potential DNA damaging factors include environmental xenobiotics, antiblastic drugs, ionizing radiations and endogenous factors, as metabolic products and reactive oxygen species. Cellular defense systems from genotoxic attack rely on phase I and II detoxification enzymes, involved in the activation, conjugation and elimination of carcinogens, and on DNA repair enzymes. There are various types of DNA damage, including base modification and adduct formation, DNA strand breaks, and DNA strand cross-links, and distinct pathways have evolved to repair them. Ineffective repair of damaged DNA in cells surviving genotoxic stress is crucial for cancer development [1].
In the last decade, several studies investigated the impact of the genetic background of the host on cancer predisposition, particularly in therapy-related AML/MDS [2]. Polymorphisms of genes encoding enzymes involved in carcinogen metabolism and DNA repair are likely to modify the risk of DNA damage and cancer development. On the other hand, these polymorphisms were shown to influence the individual response to cancer treatment, by increasing the concentration of active drug metabolites or by impairing enzymatic pathways which rescue neoplastic cells from genotoxic damage and apoptosis.
Myelodysplastic syndromes (MDS) share with other types of cancers a multistep pathogenesis, where the occurrence of several genetic and epigenetic lesions in hematopoietic progenitor cells plays a pivotal role. Genetic background may affect the individual risk of developing MDS. Few case-control studies have so far investigated the impact of genetic polymorphisms on the risk to develop MDS. In particular, Glutathione S-transferase GSTT1 and GSTM1 deletions, the methionine synthase reductase (MTRR) 66 AG genotype and the 455Asn allele of RMI1 gene have been associated to increased risk of de novo MDS [3], [4], [5], [6], [7], [8]. More interestingly, several detoxification enzyme polymorphisms, alone or in combination, such as the NAD(P)H:quinone oxidoreductase (NQO1) 187Ser allele, the CYP1A1*2A allele, the GSTP1 105Val allele, GSTT1 and GSTM1 deletions have been associated to increased risk of therapy related MDS/AML after treatment for a primary cancer [9], [10], [11].
To identify candidate genetic risk factors for MDS, we studied polymorphisms of 9 genes involved in the cellular defense pathways against genotoxic damage, including the CYP3A4-A290G promoter variant and NQO1-Pro187Ser polymorphism (phase I detoxification), Gluthatione S-Transferase GSTA1-C69T promoter variant, GSTP1-Ile105Val polymorphism, GSTM1 and GSTT1 deletions (phase II detoxification), RAD51-G135C and XRCC3-Thr241Met polymorphisms (homologous recombination of DNA double strand breaks repair), and the Xeroderma pigmentosum D (XPD) Lys751Gln polymorphism (nucleotide excision repair). Polymorphisms were correlated to patients’ clinical characteristics and survival.
Section snippets
Study population
Our study population included 160 patients (male 90, female 70, median age 71 years), diagnosed at our Hematology Department between 2002 and 2007. According to the WHO classification [12], patients were classified as: primary MDS (n = 114), including 25 (15.6%) refractory anemias (RA), 17 (10.6%) refractory anemias with ringed sideroblasts (RARS), 21 (13.1%) refractory cytopenias with multilineage dysplasia (RCMD), 6 (3.7%) refractory cytopenias with multilineage dysplasia and ringed
Genotype frequencies
In our study population, no significant differences in genotype frequencies of the detoxification enzymes CYP3A4, NQO1, GSTA1, GSTM1 and GSTT1, and of the DNA repair enzymes RAD51, XRCC3 and XPD were found between MDS patients and controls (Table 1). On the other hand, the GSTP1-105Val allele was associated to an increased risk of MDS (O.R., 1.66; 95% C.I., 1.03–2.67; p = 0.04).
No significant associations were found between enzymatic polymorphisms and patients’ characteristics, including MDS
Discussion
In our study, we found that the GSTP1-105Val allele was associated to an increased risk of MDS. Heterozygous and homozygous patients were over-represented in the MDS group, but only when combining their frequencies, the difference between patients and controls became statistically significant, likely due to the relative small size of the studied populations. The GSTP1-105Val allele has a reduced enzymatic activity compared to the GSTP1-105Ile, which may translate into decreased detoxification
Conflict of interest
None.
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Funding: This work has been supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro), M.I.U.R. (Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica) and Fondazione Roma “Progetto cellule staminali, Una nuova frontiera nella ricerca biomedica”.