Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes.

Madalene A Earp,Simon A Gayther,Chen Wang,Kate Lawrenson,Junqiang Dai,Julie M Cunningham,Qian Li,Yanina Natanzon,Ellen L Goode,Kimberly R Kalli,Stacey J Winham,S John Weroha,Brooke L Fridley,Paul Haluska,Xiaonan Hou,Rama Raghavan

doi:10.18632/oncotarget.16781

Abstract

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.

Highlights

A fusion gene, or chimera, is a hybrid gene formed from the aberrant juxtaposition of two distinct genes
We found some evidence that clear cell (CC) tumors harbor more fusions on average than any other epithelial ovarian cancer (EOC) histological type, including high-grade serous (HGS) tumors
We set out to investigate what role recurrent fusion genes may play in the tumorigenesis of EOC, the rarer EOC histological types

Summary

Introduction

A fusion gene, or chimera, is a hybrid gene formed from the aberrant juxtaposition of two distinct genes. A well-described example is BCR-ABL1, a fusion gene that confers tumor growth factor independence, inhibits apoptosis, and is the defining molecular aberration in chronic myelogenous leukemia (CML) (95% of cases) [3]. BCR-ABL1 is the target for the highly selective drug imatinib (Gleevec®), whose development is largely responsible for nearly doubling the 5-year survival time of CML patients [1, 4]. TMPRSS2-ERG has been reported in >50% of tumors, and has been used to stratify patients according to risk [8] and survival time [9]. These examples demonstrate that recurrent gene fusions have the potential for clinical benefit as drug targets and may have diagnostic and prognostic uses

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Results

Conclusion