Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS (CYCLOPS) genes have been recently identified as the most enriched class of copy-number associated gene dependencies in human cancer. These genes are cell essential and render tumor cells highly sensitive to the expression of the remaining copy. Chromophobe renal cell carcinoma (chRCC) is characterized by frequent chromosomal deletions, but the relevance of CYCLOPS genes in this tumor subtype is unclear. We found 39 (31%) of 124 recently published candidate CYCLOPS genes (B. Paolella et al., eLife 2017;6:e23268) located on 7 autosomes that are frequently lost in chRCC. GISTIC and RNA-seq data obtained from the TCGA-KICH database showed that 62% of these CYCLOPS genes had significantly lower expression levels in samples with deletion of the respective gene. As copy number (CN) loss of the CYCLOPS gene SF3B1 (Splicing factor 3B subunit 1) has been recently reported in 71% chRCC, we explored the relevance of SF3B1 CN alteration and SF3B1 expression in a set of chRCC and additional oncocytic renal neoplasms. The frequency of SF3B1 CN loss (65%) was similar to that obtained from the TCGA-KICH database and correlated significantly with both lower SF3B1 mRNA (P < .05) and protein expression (P < .001). Other tumor subtypes with oncocytic cytoplasm had normal SF3B1 CN and displayed strong SF3B1 protein expression. These results suggest that CN loss of CYCLOPS genes is a characteristic feature in chRCC. Since many CYCLOPS genes code for components of proteasomes and transcriptional regulation, their alteration could make chRCC vulnerable to targeted drugs.
Translational oncology. 2019 Jun 11 [Epub ahead of print]
Riuko Ohashi, Peter Schraml, Aashil Batavia, Silvia Angori, Patrik Simmler, Niels Rupp, Yoichi Ajioka, Esther Oliva, Holger Moch
Histopathology Core Facility, 1-757 Asahimachi-dori, Niigata University Faculty of Medicine, Chuo-ku, 951-8510 Niigata, Japan; Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, University and University Hospital Zurich, CH-8091 Zurich, Switzerland. Electronic address: ., Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, University and University Hospital Zurich, CH-8091 Zurich, Switzerland. Electronic address: ., Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, University and University Hospital Zurich, CH-8091 Zurich, Switzerland. Electronic address: ., Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, University and University Hospital Zurich, CH-8091 Zurich, Switzerland. Electronic address: ., Department of Biology, Institute of Molecular Health Sciences, Otto-Stern-Weg 7, ETH Zurich, CH-8093 Zurich, Switzerland. Electronic address: ., Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, University and University Hospital Zurich, CH-8091 Zurich, Switzerland. Electronic address: ., Histopathology Core Facility, 1-757 Asahimachi-dori, Niigata University Faculty of Medicine, Chuo-ku, 951-8510 Niigata, Japan; Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, 757 Ichibancho, Asahimachi-dori, Chuo Ward, 951-8510 Niigata, Japan. Electronic address: ., Department of Pathology, Warren Building, 55 Fruit Street, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: ., Department of Pathology and Molecular Pathology, Schmelzbergstrasse 12, University and University Hospital Zurich, CH-8091 Zurich, Switzerland. Electronic address: .