Identification of Prognostic and Susceptibility Markers in Chronic Myeloid Leukemia Using Next Generation Sequencing

Abstract

BACKGROUND: Incidence of Chronic Myeloid Leukemia (CML)is continuously increasing and expected to reach 100,000 patientsevery year by 2030. Though the discovery of Imatinib Mesylate(IM) has brought a paradigm shift in CML treatment, 20%patients show resistance to this tyrosine kinase inhibiter (TKI).Therefore, it is important to identify markers, which can predictthe occurrence and prognosis of CML. Clinical ExomeSequencing, panel of more than 4800 genes, was performed inCML patients to identify prognostic and susceptibility markers inCML.METHODS: Enrolled CML patients (n=18) were segregated as IMresponders (n=10) and IM failures (n=8) as per EuropeanLeukemia Net (ELN), 2013 guidelines. Healthy controls (n=5)were also enrolled. DNA from blood of subjects was subjected toNext Generation Sequencing. Rare mutations present in onepatient group and absent in another group were considered asprognostic markers, whereas mutations present in more than 50%patients were considered as susceptibility markers.RESULT: Mutations in genes associated with cancer relatedfunctions were found in different patient groups. Four variants:rs116201358, rs4014596, rs52897880 and rs2274329 in C8A,UNC93B1, APOH and CA6 genes, respectively, were present inIM responders; whereas rs4945 in MFGE8 was present in IMfailures. Mutations in HLA-DRB1 (rs17878951), HLA-DRB5(rs137863146), RPHN2 (rs193179333), CYP2F1 (rs116958555),KCNJ12 (rs76684759) and FUT3 (rs151218854) were present assusceptibility markers.CONCLUSION: The potential genetic markers discovered in thisstudy can help in predicting response to IM as frontline therapy.Susceptibility markers may also be used as panel for individualsprone to have CML.