General transcription factors TAF13, NC2b, GTF3BAP1 and TAF12 are specifically involved in neuroblastoma pathogenesis

C Di Pietro^a, A Rapisarda^a, T Giunta^a,a, A Grillo^b, K Mazzocco^c, A Di Cataldo^d, S Ucciardello^a,d, M Romani^c, A Messina^e, KH Grzeschik^f, GP Tonini^c, R Roeder^g, M Purrello^a

^aDipartimento di Scienze Biomediche, Sezione di Biologia e Genetica, Università di Catania, Italy, ^bLabogen, Catania, Italy, ^cIstituto Nazionale per la Ricerca sul Cancro, Genova, Italy, ^dDipartimento di Pediatria, Università di Catania, Italy, ^eDipartimento di Scienze Biomediche, Sezione di Patologia generale, Università di Catania, Italy, ^fMedizinisches Zentrum für Humangenetik, Philipps Universität, Marburg, Germany, ^gLaboratory of Biochemistry and Molecular Biology, The Rockefeller University, The Rockefeller, New York, United States

AIM: Neuroblastoma, a tumour of the sympathetic nervous system, causes about 15% of cancer deaths occurring before the age of 10 years: accordingly, it is one of the most frequent paediatric neoplasias. The weight of environmental factors is judged irrelevant, as demonstrated by the early appearance of clinical phenotype. The short arm of human chromosome 1 is one of the critical regions for its pathogenesis, that is complex and unclarified. General Transcription Factors (GTFs) have a critical role in gene expression and some of them participate in the control of proliferation and differentiation. After completing the characterisation of the genomic anatomy of the human general transcription apparatus (more than fifty genes), we have analysed the involvement of chromosome 1 short arm GTFs in the pathogenesis of neuroblastoma. METHODS AND RESULTS: Through semi-quantitative RT-PCR of sixty neuroblastoma biopsies, we have demonstrated a significative reduction of the mRNAs encoding four GTFs (TAF13, NC2b, GTF3BAP1 and TAF12, localised at 1p13, 1p22, 1p32 and 1p35, respectively) in about 60% of samples. Intriguingly, NC2b is known to be a negative modulator of cell proliferation. Since there were no quantitative variations of transcripts from two other GTF genes, GTF2B and NC2a (this last encoding the second subunit of NC2), that are localised at 1p21 - 22 and 11q13 respectively, we hypothesized that these alterations are specific and potentially important for neuroblastoma pathogenesis. This was conclusively proven by the demonstration in the same samples of Genomic Imbalance (GI) at the loci TAF13, NC2b, GTF3BAP1 and TAF12 and its absence at those for GTF2B and NC2a, obtained through ABI PRISM 310 analysis of tumour and constitutional DNA. CONCLUSIONS: Our data prove the specific involvement of NC2b, GTF3BAP1, TAF12 and TAF13 in neuroblastoma pathogenesis, at the same time suggesting that these GTFs are involved in the physiological control of cell proliferation and differentiation. Furthermore, and contrary to previous hypotheses, they also demonstrate that interstitial deletions are frequent within chromosome 1 short arm, hinting to the existence of complex selective mechanisms in neuroblastoma cells. Finally, our analysis shows a positive correlation between GTF3BAP1 mRNA reduction and advanced clinical stage, suggesting the potential value of this new marker.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 796 (Genetic instability).