TS, MTHFR AND XRCC1 GENETIC VARIANTS INFLUENCE THE OUTCOME OF MDS PATIENTS IRRESPECTIVELY OF IPSS RISK

TS, MTHFR AND XRCC1 GENETIC VARIANTS INFLUENCE THE OUTCOME OF MDS PATIENTS IRRESPECTIVELY OF IPSS RISK G. Visani1, F. Loscocco1, A. Ruzzo2, M. Voso3, E. Fabiani3, C. Finelli4, F. Graziano1, S. Barulli1, A. Volpe5, D. Magro6, P. Piccaluga7, F. Fuligni7, E. Gabucci1, E. Giacomini2, M. Vignetti8, P. Fazi8, A. Piciocchi8, M. Rocchi9, M. Magnani2, A. Isidori1 1AORMN, Hematology and Stem Cell Transplant Center, Pesaro, Italy; 2University of Urbino, Biochemistry and Molecular Biology, Urbino, Italy; 3Tor Vergata University, Hematology, Rome, Italy; 4S.Orsola-Malpighi Hospital, Hematology, Bologna, Italy; 5S.G. Moscati Hospital, Hematology and Transplant Center, Avellino, Italy; 6Pugliese-Ciacco Hospital, Hematology, Catanzaro, Italy; 7S.Orsola-Malpighi Hospital Bologna University, Experimental Diagnostic and Specialty Medicine, Bologna, Italy; 8Fondazione GIMEMA, Gruppo Italiano Malattie Ematologiche dell’Adulto, Rome, Italy; 9University of Urbino, Institute of Biomathematics, Urbino, Italy Background: Loss of genomic integrity is thought to be one of the underlying causes of myelodysplastic syndromes (MDS). We investigated the association between genetic variants in genes encoding main enzymes of BER pathway, DNA synthesis and folate metabolism and survival in MDS patients. Methods: We genotyped 113 MDS patients, 54 with IPSS low/int-1 receiving only best supportive care (BSC) (low risk group) and 59 with IPSS int-2/high treated with azacitidine (high risk group), for the following polymorphisms: XRCC1 194and 399, XRCC3 241, TS5’-UTR (2R/3R and G/C) and 3’-UTR (6bp+/6bp-), MTHFR 677 and1298, APE1 148. OS was calculated using the Kaplan-Meier estimate probabilities, and differences between survival curves were analyzed by the log-rank test. The association between genetic variants and survival was assessed using stepwise logistic regression model. Results: The median period of observation was 27 months for low/ int-1 risk group and 13 months for int-2/high risk group. In the low risk group, XRCC1 399 GG [Hazard ratio (HR)=4.65; p=0.05], TS3’-UTR -6/-6 (HR=7.07; p=0.02), TS5’-UTR 2R/3G, 3C/3G, 3G/3G (HR=11.44; p=0.02) and MTHFR 677 TT (HR=67.12; p=0.0001) genotypes were associated with a shorter survival if compared to the reference group of variant alleles. We then analyzed the high risk group, and we found that 3 out of the 4 genotypes associated with an adverse outcome in the lower group were still significantly associated to lower survival [XRCC1 399 GG (HR=5.71 p=0.002), MTHFR677 TT (HR=8.58 p=0.0001), TS3’-UTR +6/+6 (HR=0.097 p=0.004), this latter with a protective role]. Finally, we performed an exploratory analysis to investigate the effect on survival of the combination of the unfavorable genotypes to each other. In the low risk group, the 3-year OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles. The predictive role of the adverse genotypes combination on survival was confirmed also in the high risk group. Interestingly, treatment with azacitidine conferred a survival advantage to patients with unfavorable genetic variants, resulting in the absence of a statistical difference in survival between low-risk patients treated with BSC only and high-risk patients treated with azacitidine. Conclusions: These data suggest, for the first time, that genetic variants in TS, MTHFR and XRCC1 genes could independently modulate OS of MDS patients, representing a possible new prognostic biomarkers able to provide guidance for clinical management of MDS patients.