Identification of differentially expressed genes related to NF1-associated malignant transformation from a patient with neurofibromatosis type 1.

Abstract

Neurofibromatosis type 1 (NF1) is one of the most common inherited autosomal dominant disorders. Malignant peripheral nerve sheet tumors (MPNSTs) represent a major cause of mortality in NF1 patients. To identify the genes involved in malignant transformation of benign neurofibromas, we performed whole gene expression comparison study with three types of tissues, pathologically normal, benign, and malignant tissues, obtained from a patient with NF1. Using ACP (annealing controlled primer)-based PCR method, GeneFishing DEG (differentially expressed gene) screening, we found a total of 20 DEGs that showed clear differences in expression patterns; compared to normal tissue, 11 DEGs in benign and/or malignant tumors showing up-regulation of gene expression and 9 DEGs in benign and malignant tumors showing down-regulation. Sequence analysis of the 20 DEGs revealed that 16 of them were already known genes that are related closely to tumorigenesis and/or tumor progression, and the remaining 4 genes were unknown. Two of 16 DEGs were the same gene, IFITM1. Fifteen genes identified included TNXB, DHRS3 and SERPINE1 genes, the expression of which had previously been known to change in NF1 tumors. Validation of the identified genes was carried out by RT-PCR using gene-specific primers and Western blot analysis and demonstrated the efficacy and accuracy of the GeneFishing screening study. Here, we highlight three candidate genes, SERPINE1, IFITM1 and ATP2A2, that are related with interferon-γ, and suggest them as candidate genes involved in malignant transformation of benign neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs) in this NF1 patient. Further studies are necessary to elucidate the genetic or epigenetic mechanisms of these genes in tumor progression of NF1.