Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes
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Madalene A. Earp1, Rama Raghavan2, Qian Li2,10, Junqiang Dai2, Stacey J. Winham1, Julie M. Cunningham3, Yanina Natanzon1, Kimberly R. Kalli4, Xiaonan Hou5, S. John Weroha5,6, Paul Haluska5,6, Kate Lawrenson7, Simon A. Gayther8,9, Chen Wang1, Ellen L. Goode1,* and Brooke L. Fridley2,10,*
1Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
2Department of Biostatistics, University of Kansas Medical Center, KS, USA
3Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
4Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
5Department of Oncology, Mayo Clinic, Rochester, MN, USA
6Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
7Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
8Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
9Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
10Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
*These authors contributed equally to this work
Brooke L. Fridley, email: Brooke.Fridley@moffitt.org
Keywords: fusion gene, ovarian cancer, RNA-sequencing, histological subtypes, TCGA
Received: August 08, 2016 Accepted: March 22, 2017 Published: April 01, 2017
Gene fusions play a critical role in some cancers and can serve as important clinical targets. In epithelial ovarian cancer (EOC), the contribution of fusions, especially by histological type, is unclear. We therefore screened for recurrent fusions in a histologically diverse panel of 220 EOCs using RNA sequencing. The Pipeline for RNA-Sequencing Data Analysis (PRADA) was used to identify fusions and allow for comparison with The Cancer Genome Atlas (TCGA) tumors. Associations between fusions and clinical prognosis were evaluated using Cox proportional hazards regression models. Nine recurrent fusions, defined as occurring in two or more tumors, were observed. CRHR1-KANSL1 was the most frequently identified fusion, identified in 6 tumors (2.7% of all tumors). This fusion was not associated with survival; other recurrent fusions were too rare to warrant survival analyses. One recurrent in-frame fusion, UBAP1-TGM7, was unique to clear cell (CC) EOC tumors (in 10%, or 2 of 20 CC tumors). We found some evidence that CC tumors harbor more fusions on average than any other EOC histological type, including high-grade serous (HGS) tumors. CC tumors harbored a mean of 7.4 fusions (standard deviation [sd] = 7.4, N = 20), compared to HGS EOC tumors mean of 2.0 fusions (sd = 3.3, N = 141). Few fusion genes were detected in endometrioid tumors (mean = 0.24, sd = 0.74, N = 55) or mucinous tumors (mean = 0.25, sd = 0.5, N = 4) tumors. To conclude, we identify one fusion at 10% frequency in the CC EOC subtype, but find little evidence for common (> 5% frequency) recurrent fusion genes in EOC overall, or in HGS subtype-specific EOC tumors.
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