The landscape of tumor suppressors in primary tumors. P. Van Loo1,2,3, J. Cheng4,5, H. K. M. Vollan6,7,8 1) Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; 2) Center for the Biology of Disease, VIB, Leuven, Belgium; 3) Department of Human Genetics, University of Leuven, Leuven, Belgium; 4) SCD-SISTA, Department of Electrical Engineering - ESAT, University of Leuven, Leuven, Belgium; 5) iMinds Future Health Department, University of Leuven, Leuven, Belgium; 6) Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 7) The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; 8) Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.

   Homozygous deletions are rare in cancers and often target tumor suppressors. We are performing a systematic screen of homozygous deletions in a compendium of 14,000 human cancers, aiming to identify known and novel tumor suppressors. Such a systematic screen has so far been performed only in cell lines, as non-aberrant cell infiltration has historically hindered the reliable identification of homozygous deletions in primary tumors. Results on a pilot series of 2218 primary tumors across 12 human cancers identified 89 genomic regions recurrently targeted by homozygous deletions. These recurrent homozygous deletions occurred either over tumor suppressors or over regions of increased genomic instability called fragile sites. We constructed a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions that therefore are likely to contain tumor suppressors. From the patterns of the homozygous deletions, the patterns of mutations in COSMIC and the literature, we subsequently identified candidate tumor suppressors.
    Our pilot screen identified 11 established tumor suppressors and discovered 25 candidate tumor suppressors. Our results add to the emerging evidence of several genes recently proposed in the literature as tumor suppressors (including FAT1, BIRC2/BIRC3, TET1 and MGMT), and bring forward several novel candidate tumor suppressors (including CASP3, CASP9, RAD17, BAZ1A, CPEB3 and SETD1B). Interestingly, we observed four peaks of homozygous deletions around the ubiquitin specific proteases USP34, USP29, USP44 and the neighboring genes USP8 and USP50, predominantly in lung cancer. These are all family members of a large group of deubiquitinating enzymes that prevent protein degradation by the proteasome. Interestingly, p53 has been described as a target of USP29 and USP34 has been linked to Wnt signaling. In addition, USP44 regulates the mitotic cell cycle checkpoint and Usp44 knockout mice spontaneously formed lung tumors. Therefore, our results further establish USP44 as a tumor suppressor in lung cancer, and implicate other ubiquitin specific proteases in oncogenesis as well.
    In summary, through copy-number meta-analysis of large-genomic datasets, our study is significantly advancing the landscape of tumor suppressors.