Prevalence of FLT3, NPM1 and CEBPA Mutations and Correlation to Haematological Parameters in Newly Diagnosed Adult Acute Myeloid Leukaemia Patients in North and Northeast Regions of Peninsular Malaysia

Izaz Ul Haq, Mat Jusoh Siti Asmaa, Shafini Mohamed Yusoff, Azlan Husin, Ai Sim Goh, Noria Abdul Mutalib, Badrul Hisham Yahaya, Muhamad Farid Johan, Abdul Rahim Hussein

Abstract


Acute myeloid leukaemia (AML) is a clinically heterogeneous haematological cancer with increased incidence in the elderly. Genetic mutations remain important prognostic factors for treatment outcome. Our study determined the prevalence and clinical significance of FLT3, NPM1, and CEBPA mutations of AML in the Northern and East Coast of Peninsular Malaysia. Forty-seven de-novo adult patientswere analysed for 3 common classical mutations in AML; FLT3 (exons 14-15 and 20), NPM1 (exon 12), and CEBPA (exon 1) by polymerase chain reaction (PCR), Conformation Sensitive Gel Electrophoresis (CSGE) and Sanger sequencing. The CSGE analysis revealed the following mutation combinations; NPM1+/FLT3-/CEBPA- (17.0%), NPM1-/FLT3-/CEBPA+ (10.6%), FLT3+/NPM1-/CEBPA-(4.3%), NPM1-/FLT3+/CEBPA+ (4.3%), and NPM1+/FLT3+/CEBPA- (2.1%). c.71666delC, c.71674T>A and c.71683insA mutations were identified in 80%, 60% and 40%, respectively, in addition to FLT3-ITD; while c.28026delA (n=3) and c.27837insCAGA (n=4) in NPM1;c.5699_5700insACCCGC (n=2) and c.5711C>G (n=2) in CEBPA. FLT3-ITD and CEBPA mutations were significantly correlated with higher blast percentage (p=0.045), higher WBC count (p=0.005), and higher platelet count (p=0.001). NPM1-/FLT3+/CEBPA- (1.0%), NPM1-/FLT3-/CEBPA+ (0.8%) and NPM1+/FLT3-/CEBPA- (0.5%) have the longest one-year cumulative overall survival (OS), but not significant (p>0.05). The different types of molecular variants found within the FLT3, NPM1 and CEBPA hotspots, hinting intraclonal diversities which their translocated proteins display distinct features for future prognosis of AML.

Keywords


AML, FLT3, NPM1, CEBPA, mutational analysis

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