Contributions
Abstract: PB1911
Type: Publication Only
Background
Myelodysplastic syndrome (MDS) is a heterogeneous group of hematopoietic stem cell disorders, characterized by peripheral cytopenias, ineffective hematopoiesis and frequent transformation into acute myeloid leukemia (AML). Several mechanisms are involved in disease development and progression as a consequence of stepwise accumulation of DNA mutations, which infers a defect in DNA repair mechanisms. Mutations in DNA repair genes of the nucleotide excision repair (NER) group, and affecting the mismatch repair (MMR), and DNA crosslink repair genes, among others, are the cause of inherited cancer syndromes. On the other hand, genetic variants in genes involved in these mechanisms have been identified for their potential role in cancer susceptibility. However, in MDS, the relevance of these variants remains to be fully established and correlated with prognosis.
Aims
In the present study we investigate the influence of polymorphisms in DNA repair genes (XRCC5, RMI1, RAD52, XRCC3, BLM, TOP3A, OGG1, LIG1, ERCC2, and MSH3) as risk factor for MDS development as well as prognostic factors of acute leukemia transformation.
Methods
We performed a hospital-based case control-study to investigate the association of DNA repair genes with MDS susceptibility and prognosis in a group of Portuguese patients. To that end, we genotyped by TaqMan real-time PCR 10 SNPs (one per gene: XRCC5, RMI1, RAD52, XRCC3, BLM, TOP3A, OGG1, LIG1, ERCC2, and MSH3) in 60 MDS patients and 120 age-sex matched controls. Frequencies of alleles, genotypes, and genotypic profiles were estimated and compared between patients and controls. The role of these genes in MDS susceptibility was studied by logistic regression analysis. The influence in MDS prognosis was evaluated by estimating, through Kaplan Meier analysis, the rate of MDS transformation into AML and the overall survival.
Results
There was no significant difference in frequencies of XRCC5, RMI1, RAD52, XRCC3, BLM, TOP3A, OGG1, LIG1 and ERCC2 variants between patients and controls. In contrary, we found that heterozygous individuals for MSH3 c.2655+5137C>G had an increased susceptibility to MDS development (OR = 6.882, 95% CI 1.789-26.479, p < 0.003), being the increased risk attributed to G allele (OR = 6.405, 95% CI 1.552 30.469, p < 0.003). In addition, MDS patients homozygous for BLM c.-4-889A>C showed higher rate of MDS transformation into AML (HR = 7.646, 95% CI 1.362 24467, p < 0.023).
Conclusion
The present study suggests that MSH3 c.2655+5137C>G variant influences MDS susceptibility, and BLM c.-4-889A>C variant may be implicated in the propensity to AML transformation observed in MDS patients. Thus, these gene variants could be used as a risk and prognostic biomarkers for MDS, if these associations were replicated in a larger case-control study and/or with other populations.
Session topic: 9. Myelodysplastic syndromes - Biology
Keyword(s): prognosis, Polymorphism, Myelodysplasia, DNA repair
Abstract: PB1911
Type: Publication Only
Background
Myelodysplastic syndrome (MDS) is a heterogeneous group of hematopoietic stem cell disorders, characterized by peripheral cytopenias, ineffective hematopoiesis and frequent transformation into acute myeloid leukemia (AML). Several mechanisms are involved in disease development and progression as a consequence of stepwise accumulation of DNA mutations, which infers a defect in DNA repair mechanisms. Mutations in DNA repair genes of the nucleotide excision repair (NER) group, and affecting the mismatch repair (MMR), and DNA crosslink repair genes, among others, are the cause of inherited cancer syndromes. On the other hand, genetic variants in genes involved in these mechanisms have been identified for their potential role in cancer susceptibility. However, in MDS, the relevance of these variants remains to be fully established and correlated with prognosis.
Aims
In the present study we investigate the influence of polymorphisms in DNA repair genes (XRCC5, RMI1, RAD52, XRCC3, BLM, TOP3A, OGG1, LIG1, ERCC2, and MSH3) as risk factor for MDS development as well as prognostic factors of acute leukemia transformation.
Methods
We performed a hospital-based case control-study to investigate the association of DNA repair genes with MDS susceptibility and prognosis in a group of Portuguese patients. To that end, we genotyped by TaqMan real-time PCR 10 SNPs (one per gene: XRCC5, RMI1, RAD52, XRCC3, BLM, TOP3A, OGG1, LIG1, ERCC2, and MSH3) in 60 MDS patients and 120 age-sex matched controls. Frequencies of alleles, genotypes, and genotypic profiles were estimated and compared between patients and controls. The role of these genes in MDS susceptibility was studied by logistic regression analysis. The influence in MDS prognosis was evaluated by estimating, through Kaplan Meier analysis, the rate of MDS transformation into AML and the overall survival.
Results
There was no significant difference in frequencies of XRCC5, RMI1, RAD52, XRCC3, BLM, TOP3A, OGG1, LIG1 and ERCC2 variants between patients and controls. In contrary, we found that heterozygous individuals for MSH3 c.2655+5137C>G had an increased susceptibility to MDS development (OR = 6.882, 95% CI 1.789-26.479, p < 0.003), being the increased risk attributed to G allele (OR = 6.405, 95% CI 1.552 30.469, p < 0.003). In addition, MDS patients homozygous for BLM c.-4-889A>C showed higher rate of MDS transformation into AML (HR = 7.646, 95% CI 1.362 24467, p < 0.023).
Conclusion
The present study suggests that MSH3 c.2655+5137C>G variant influences MDS susceptibility, and BLM c.-4-889A>C variant may be implicated in the propensity to AML transformation observed in MDS patients. Thus, these gene variants could be used as a risk and prognostic biomarkers for MDS, if these associations were replicated in a larger case-control study and/or with other populations.
Session topic: 9. Myelodysplastic syndromes - Biology
Keyword(s): prognosis, Polymorphism, Myelodysplasia, DNA repair