Ádám Nagy1,2, Balázs Győrffy1,2
1 MTA TTK Institute of Enzymology Lendület Cancer Biomarker Research Group, Magyar Tudósok körútja 2., 1117, Budapest, Hungary
2 Semmelweis University 2nd Dept. of Pediatrics, Tűzoltó utca 7-9., 1094, Budapest, Hungary
Introduction & Aims. Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells and the most common malignant myeloid disorder in adults. There are several gene mutations – such as IDH1, IDH2, FLT3, and NPM1 – that serve a major role in the differentiation and the progression of AML. Our aim was to identifying genes whose expression is associated with driver mutations and survival outcome.
Methods. Our analysis was based on four analysis cohorts: one training set and three validation set. GSE6891 was used as a training that was downloaded from NCBI GEO database. GSE1159 (NCBI GEO) and TCGA (The Cancer Genome Atlas repository) samples were used as a validation cohort. We selected those patients who had both mutation and gene expression data. Wilcoxon analysis was used to identifying genes showing expression affected by mutations. Cox regression analysis was performed to examine the association between gene expression and survival outcome. Data processing and statistical computation were performed in R statistical environment.
Results. We identified 70, 77, 80, and 182 significantly altered genes in the IDH1, IDH2, FLT3, and NPM1 mutant cohorts, respectively. These mutations are associated with gene expression alteration of numerous genes, of which the most robust are the RASGRP3 in the IDH1 mutant cohort, HOXA10, HOXB5 and ITM2A in the NPM1 mutant cohort. Cox regression analysis showed that the expression of some mutation associated genes were correlated with overall survival - RASGRP3 (HR=0.76, p=0.018), HOXA10 (HR=0.54, p=1.6E-05), HOXB5 (HR=0.73, p=0.0099) and ITM2A (HR=1.5, p=0.0046).
Conclusions. We identified genes that were linked to somatic mutations of IDH1, IDH2, FLT3 and NPM1 genes by computationally linking genotype and gene expression. Validation of these genes by in vitro measurements reveals their potential therapeutic benefit in AML.
Doctoral School: Pathology
Supervisor: Balázs Győrffy
E-mail address: email@example.com