Ting Wei1, Ji Lu2, Tao Ma1, Haojie Huang3, Jean-Pierre Kocher1, Liguo Wang1,3,4. 1. Division of Computational Biology, College of Medicine and Science, Mayo Clinic, Rochester, MN, USA. 2. Department of Urology, The First Hospital of Jilin University, Changchun, People's Republic of China. 3. Department of Biochemistry and Molecular Biology, College of Medicine and Science, Mayo Clinic, Rochester, MN, USA. 4. Bioinformatics and Computational Biology Graduate Program, University of Minnesota Rochester, Rochester, MN, USA.
Abstract
BACKGROUND: Thousands of gene fusions have been reported in prostate cancer, but their authenticity, incidence, and tumor specificity have not been thoroughly evaluated, nor have their genomic characteristics been carefully explored. METHODS: We developed FusionVet to dedicatedly validate known fusion genes using RNA-seq alignments. Using FusionVet, we re-assessed 2727 gene fusions reported from 36 studies using the RNA-seq data generated by The Cancer Genome Atlas (TCGA). We also explored their genomic characteristics and interrogated the transcriptomic and DNA methylomic consequences of the E26 transformation-specific (ETS) fusions. RESULTS: We found that nearly two-thirds of reported fusions are intra-chromosomal, and 80% of them were formed between 2 protein-coding genes. Although most (76%) genes were fused to only 1 partner, we observed many fusion hub genes that have multiple fusion partners, including ETS family genes, androgen receptor signaling pathway genes, tumor suppressor genes, and proto-oncogenes. More than 90% of the reported fusions cannot be validated by TCGA RNA-seq data. For those fusions that can be validated, 5% were detected from tumor and normal samples with similar frequencies, and only 4% (120 fusions) were tumor-specific. The occurrences of ERG, ETV1, and ETV4 fusions were mutually exclusive, and their fusion statuses were tightly associated with overexpressions. Besides, we found ERG fusions were significantly co-occurred with PTEN deletion but mutually exclusive with common genomic alterations such as SPOP mutation and FOXA1 mutation. CONCLUSIONS: Most of the reported fusion genes cannot be validated by TCGA samples. The ETS family and androgen response genes were significantly enriched in prostate cancer-specific fusion genes. Transcription activity was significantly repressed, and the DNA methylation was significantly increased in samples carrying ERG fusion.
BACKGROUND: Thousands of gene fusions have been reported in prostate cancer, but their authenticity, incidence, and tumor specificity have not been thoroughly evaluated, nor have their genomic characteristics been carefully explored. METHODS: We developed FusionVet to dedicatedly validate known fusion genes using RNA-seq alignments. Using FusionVet, we re-assessed 2727 gene fusions reported from 36 studies using the RNA-seq data generated by The Cancer Genome Atlas (TCGA). We also explored their genomic characteristics and interrogated the transcriptomic and DNA methylomic consequences of the E26 transformation-specific (ETS) fusions. RESULTS: We found that nearly two-thirds of reported fusions are intra-chromosomal, and 80% of them were formed between 2 protein-coding genes. Although most (76%) genes were fused to only 1 partner, we observed many fusion hub genes that have multiple fusion partners, including ETS family genes, androgen receptor signaling pathway genes, tumor suppressor genes, and proto-oncogenes. More than 90% of the reported fusions cannot be validated by TCGA RNA-seq data. For those fusions that can be validated, 5% were detected from tumor and normal samples with similar frequencies, and only 4% (120 fusions) were tumor-specific. The occurrences of ERG, ETV1, and ETV4 fusions were mutually exclusive, and their fusion statuses were tightly associated with overexpressions. Besides, we found ERG fusions were significantly co-occurred with PTEN deletion but mutually exclusive with common genomic alterations such as SPOP mutation and FOXA1 mutation. CONCLUSIONS: Most of the reported fusion genes cannot be validated by TCGA samples. The ETS family and androgen response genes were significantly enriched in prostate cancer-specific fusion genes. Transcription activity was significantly repressed, and the DNA methylation was significantly increased in samples carrying ERG fusion.
Authors: Bo Han; Rohit Mehra; Saravana M Dhanasekaran; Jindan Yu; Anjana Menon; Robert J Lonigro; Xiaosong Wang; Yusong Gong; Lei Wang; Sunita Shankar; Bharathi Laxman; Rajal B Shah; Sooryanarayana Varambally; Nallasivam Palanisamy; Scott A Tomlins; Chandan Kumar-Sinha; Arul M Chinnaiyan Journal: Cancer Res Date: 2008-09-15 Impact factor: 12.701
Authors: Christiaan Klijn; Steffen Durinck; Eric W Stawiski; Peter M Haverty; Zhaoshi Jiang; Hanbin Liu; Jeremiah Degenhardt; Oleg Mayba; Florian Gnad; Jinfeng Liu; Gregoire Pau; Jens Reeder; Yi Cao; Kiran Mukhyala; Suresh K Selvaraj; Mamie Yu; Gregory J Zynda; Matthew J Brauer; Thomas D Wu; Robert C Gentleman; Gerard Manning; Robert L Yauch; Richard Bourgon; David Stokoe; Zora Modrusan; Richard M Neve; Frederic J de Sauvage; Jeffrey Settleman; Somasekar Seshagiri; Zemin Zhang Journal: Nat Biotechnol Date: 2014-12-08 Impact factor: 54.908
Authors: Gisele H J M Leyten; Daphne Hessels; Frank P Smit; Sander A Jannink; Hans de Jong; Willem J G Melchers; Erik B Cornel; Theo M de Reijke; Henk Vergunst; Paul Kil; Ben C Knipscheer; Christina A Hulsbergen-van de Kaa; Peter F A Mulders; Inge M van Oort; Jack A Schalken Journal: Clin Cancer Res Date: 2015-03-18 Impact factor: 12.531
Authors: Yan P Yu; Ying Ding; Zhanghui Chen; Silvia Liu; Amantha Michalopoulos; Rui Chen; Zulfiqar G Gulzar; Bing Yang; Kathleen M Cieply; Alyssa Luvison; Bao-Guo Ren; James D Brooks; David Jarrard; Joel B Nelson; George K Michalopoulos; George C Tseng; Jian-Hua Luo Journal: Am J Pathol Date: 2014-10 Impact factor: 4.307
Authors: Paula Paulo; João D Barros-Silva; Franclim R Ribeiro; João Ramalho-Carvalho; Carmen Jerónimo; Rui Henrique; Guro E Lind; Rolf I Skotheim; Ragnhild A Lothe; Manuel R Teixeira Journal: Genes Chromosomes Cancer Date: 2011-11-12 Impact factor: 5.006
Authors: Joost L Boormans; Hanneke Korsten; Angelique J C Ziel-van der Made; Geert J L H van Leenders; Carola V de Vos; Guido Jenster; Jan Trapman Journal: Int J Cancer Date: 2013-02-12 Impact factor: 7.396
Authors: Sunita R Setlur; Kirsten D Mertz; Yujin Hoshida; Francesca Demichelis; Mathieu Lupien; Sven Perner; Andrea Sboner; Yudi Pawitan; Ove Andrén; Laura A Johnson; Jeff Tang; Hans-Olov Adami; Stefano Calza; Arul M Chinnaiyan; Daniel Rhodes; Scott Tomlins; Katja Fall; Lorelei A Mucci; Philip W Kantoff; Meir J Stampfer; Swen-Olof Andersson; Eberhard Varenhorst; Jan-Erik Johansson; Myles Brown; Todd R Golub; Mark A Rubin Journal: J Natl Cancer Inst Date: 2008-05-27 Impact factor: 13.506
Authors: Tingting Gong; Weerachai Jaratlerdsiri; Jue Jiang; Cali Willet; Tracy Chew; Sean M Patrick; Ruth J Lyons; Anne-Maree Haynes; Gabriela Pasqualim; Ilma Simoni Brum; Phillip D Stricker; Shingai B A Mutambirwa; Rosemarie Sadsad; Anthony T Papenfuss; Riana M S Bornman; Eva K F Chan; Vanessa M Hayes Journal: Genome Med Date: 2022-08-31 Impact factor: 15.266