Role of Molecular Mutations, Telomerase and Promoter Methylation Status of the TSGs (p15INK4b, SOCS-1, Calcitonin and FHIT) in Disease Severity, Progression and Survival in a Series of 100 MDS Patients: A Study from India

Abstract

In contrast to the Western countries, Myelodysplastic syndromes (MDS) in India is being increasingly seen in young adults. The severity of the disease is more in Indian patients at time of presentation; moreover their response to treatment is poor. In the present study molecular markers which may affect the biology of MDS patients were studied.Conventional cytogenetics, molecular mutations of RAS and FLT3 genes, hTERT gene expression, telomerase activity (TA) and promoter methylation status of four tumor suppressor genes (TSGs) (p15INK4b, SOCS-1, calcitonin and FHIT) were analyzed in a series of 100 MDS patients and correlated with disease severity, progression and survival. It was found that the prevalence of MDS was higher in patients with age<60 years as compared to the patients with age ≥ 60 years (75% vs. 25%). Normal cytogenetics was present in 26/51 (51%) patients and 25/51 (49%) patients had chromosomal abnormalities. The frequency of N-RAS mutation was 3% and K-RAS mutation was 9%. FLT3-ITD and FLT3-TKD mutations were absent. TA was increased in 17/100 (17%) cases. hTERT expression was present in 17/100 (17%) cases. 40 patients (40%) had p15INK4b gene methylation. p15INK4b, SOCS-1, FHIT and calcitonin gene methylation was observed in 40 (40%), 53 (53%), 43 (43%) and 58 (58%) patients respectively. After multivariate analysis, only p15INK4b gene methylation was found as an independent predictor for progression of disease in MDS patients. In conclusion, p15INK4b gene methylation may play pivotal role in the diagnosis and disease progression in younger Indian MDS patients.