Journal Article

A Novel Translocation Breakpoint within the BPTF Gene Is Associated with a Pre-Malignant Phenotype

Polak-Charcon, Sylvie, Solomon, Hilla, Goldfinger, Naomi, Rotter, Varda, Goldstein, Ido, Lipson, Doron, Yakhini, Zohar, Barshack, Iris, Kalo, Eyal, Madar, Shalom, Mardoukh, Corine, Navon, Roy, Buganim, Yosef, Brosh, Ran, Milyavsky, Michael, Perelman, Marina

2010

Overview

Partial gain of chromosome arm 17q is an abundant aberrancy in various cancer types such as lung and prostate cancer with a prominent occurrence and prognostic significance in neuroblastoma--one of the most common embryonic tumors. The specific genetic element/s in 17q responsible for the cancer-promoting effect of these aberrancies is yet to be defined although many genes located in 17q have been proposed to play a role in malignancy. We report here the characterization of a naturally-occurring, non-reciprocal translocation der(X)t(X;17) in human lung embryonal-derived cells following continuous culturing. This aberrancy was strongly correlated with an increased proliferative capacity and with an acquired ability to form colonies in vitro. The breakpoint region was mapped by fluorescence in situ hybridization (FISH) to the 17q24.3 locus. Further characterization by a custom-made comparative genome hybridization array (CGH) localized the breakpoint within the Bromodomain PHD finger Transcription Factor gene (BPTF), a gene involved in transcriptional regulation and chromatin remodeling. Interestingly, this translocation led to elevation in the mRNA levels of the endogenous BPTF. Knock-down of BPTF restricted proliferation suggesting a role for BPTF in promoting cellular growth. Furthermore, the BPTF chromosomal region was found to be amplified in various human tumors, especially in neuroblastomas and lung cancers in which 55% and 27% of the samples showed gain of 17q24.3, respectively. Additionally, 42% percent of the cancer cell lines comprising the NCI-60 had an abnormal BPTF locus copy number. We suggest that deregulation of BPTF resulting from the translocation may confer the cells with the observed cancer-promoting phenotype and that our cellular model can serve to establish causality between 17q aberrations and carcinogenesis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Aberration / Antigens, Nuclear - metabolism / Base Sequence / Biology / Breast cancer / Cancer / Carcinogenesis / Carcinogens / Cell Proliferation / Chromatin remodeling / Chromosome 17 / Chromosomes / Chromosomes, Human, Pair 17 / Cloning / Colonies / Comparative Genomic Hybridization - methods / Copy number / Cytogenetics / Deregulation / Drosophila / Embryos / Fluorescence / Fluorescence in situ hybridization / Gene expression / Gene regulation / Genes / Genetic aspects / Genetics and Genomics/Cancer Genetics / Genetics and Genomics/Comparative Genomics / Genomes / Genomics / Genotype & phenotype / Humans / Hybridization / In Situ Hybridization, Fluorescence / Insects / Kinases / Leukemia / Ligands / Loci / Lung - embryology / Lung cancer / Lung Neoplasms - genetics / Malignancy / Models, Genetic / Molecular Sequence Data / Nerve Tissue Proteins - metabolism / Neuroblastoma / Neuroblastoma - metabolism / Oncology/Lung Cancer / Pathology / Phenotype / Prostate cancer / Protein Structure, Tertiary / Proteins / Science / Thyroid gland / Transcription (Genetics) / Transcription Factors - metabolism / Translocation / Translocation, Genetic / Trisomy / Tumor cell lines / Tumors