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Integrative Copy Number Analysis of Uveal Melanoma Reveals Novel Candidate Genes Involved in Tumorigenesis Including a Tumor Suppressor Role for PHF10/ Baf45a

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Integrative Copy Number Analysis of Uveal Melanoma Reveals Novel Candidate Genes Involved in Tumorigenesis Including a Tumor Suppressor Role for PHF10/ Baf45a Author Manuscript Published OnlineFirst on June 21, 2019; DOI: 10.1158/1078-0432.CCR-18-3052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Integrative copy number analysis of uveal melanoma reveals novel candidate genes involved in tumorigenesis including a tumor suppressor role for PHF10/ BAF45a Running title: Copy number analysis reveals novel UM candidate genes Hima Anbunathan1, Ruth Verstraten1,2, A. Singh3, J. William Harbour4, Anne M. Bowcock1,2,5 1National Heart and Lung Institute, Imperial College, London, SW3 6LY, United Kingdom 2Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, U.S.A. 3Dept. of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, U.S.A. 4Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, U.S.A. 5Departments Dermatology and Genetics & Genome Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, U.S.A. Correspondence to: A.M. Bowcock, Email: [email protected] Departments of Oncological Sciences, Dermatology and Genetics & Genome Sciences, Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place Box 1130 New York, NY 10029 T: (212) 659-8256 F: (212) 987-2240 Key words: uveal melanoma, copy number alteration, transcriptome, exome sequencing, PHF10, PTK2 1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 21, 2019; DOI: 10.1158/1078-0432.CCR-18-3052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Purpose: Uveal melanoma (UM) is a primary malignancy of the eye with oncogenic mutations in GNAQ, GNA11, or CYSLTR2, and additional mutations in BAP1 (usually associated with LOH of Chr 3), SF3B1 or EIF1AX. There are other characteristic chromosomal alterations, but their significance is not clear. Experimental Design: To investigate genes driving chromosomal alterations we integrated copy number, transcriptome and mutation data from three cohorts and followed up key findings. Results: We observed significant enrichment of transcripts on Chromosomes 1p, 3, 6, 8 and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27 and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27 we identified two tumors with homozygous deletion of PHF10/BAF45a and one with a frameshift mutation with concomitant loss of the wild type allele. Down-regulation of PHF10 in UM cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for PHF10 as a novel tumor suppressor at Chr 6q27. Conclusions: Integration of copy number, transcriptome and mutation data revealed novel candidate genes playing a role in UM pathogenesis and a potential tumor suppressor role for PHF10. 2 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 21, 2019; DOI: 10.1158/1078-0432.CCR-18-3052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance Here we describe integration of copy number, transcriptomic, epigenomic and mutational data in uveal melanoma across three independent datasets. Although loss of one copy of Chromosome 3 is usually accompanied by loss of function mutations in BAP1, the significance of other chromosomal changes such as loss of Chr 1p, 6q and 8p, and gain of Chr 6p and 8q are not clear. We describe candidate genes on altered chromosomes affecting uveal melanoma pathogenesis and patient survival. We also provide evidence for a tumor suppressor role for PHF10 on Chr 6q27. Its loss affects early pathways in cell development such as transcriptional regulation as well as adhesion and migration. This knowledge will be important as we progress towards a more comprehensive molecular diagnosis of uveal melanoma and determination of prognosis. Besides providing important insights in the development of uveal melanoma these studies provide novel therapeutic targets for this cancer. 3 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 21, 2019; DOI: 10.1158/1078-0432.CCR-18-3052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Uveal melanoma (UM) is the most common primary intraocular malignant tumor diagnosed in approximately six cases per million per year. Approximately 40% of patients develop metastatic melanoma to the liver within ten years (1). Advances made in the local methods of treatment of primary uveal melanoma have not led to an improvement in survival and after metastasis there is a median survival time of less than six months (2). UMs display characteristic genomic signatures including recurrent chromosomal aberrations, gene mutations and gene expression profiles (GEP), some of which are predictive of metastatic risk (3,4). Mutations in GNAQ, GNA11, CYSLTR2 and PLCB4 that constitutively activate Gq signaling are seen in almost all tumors in a mutually exclusive manner (5-8). Inactivating mutations in BAP1 at Chromosome 3p21 (9) are found in tumors with loss of heterozygosity for Chr 3 (LOH3) and a GEP predictive of metastatic risk (class 2 tumors) (10), and mutations in SF3B1 or EIF1AX are found in tumors with disomy 3 and a GEP associated with an intermediate and low likelihood of metastasis respectively (class 1 tumors) (4,11,12). Whole genome sequencing has also revealed potential mutations in other genes (13). In addition to LOH3, UMs are characterized by chromosomal alterations that can include Chr 1p loss, 6p gain, 6q loss, 8p loss, 8q gain, and 16q loss (14-20). These DNA copy number aberrations (CNAs) are an important category of genetic alterations which can lead to development and progression of cancers by affecting gene dosage, sometimes amplifying genes conferring a proliferative or metastatic advantage or leading to loss of function of tumor suppressor genes. However, the significance of CNAs in most cancers, including in UM is poorly understood. A global characterization of copy number, transcriptome, mutation, and methylation status in UM has been described (20). This confirmed much previous work and showed four distinct 4 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 21, 2019; DOI: 10.1158/1078-0432.CCR-18-3052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. molecular subtypes of CNA, each associated with a varying degree of metastatic risk. Here, we describe copy number analysis of 182 tumor samples from three different cohorts followed by integration of transcriptomic, methylation and mutation data to look for genes driving copy number loss or gain, extending earlier studies investigating the relationship with chromosomal alterations and gene expression in UM with microarrays (21). We describe candidate genes on chromosomes 1p, 8q and 6q and provide evidence for a tumor suppressor role for PHF10 mapping to Chr 6q27. Functional studies provided insights into the consequences of loss of PHF10. Materials and Methods Data source and analysis Data from 182 primary UM tumor samples were obtained from three different cohorts: Washington University (WU), Cleveland Clinic (CC) and TCGA. All of the samples were enucleated specimens obtained from adult patients after they had provided written informed consent. Studies were conducted in accordance with recognized ethical guidelines (e.g., Declaration of Helsinki, CIOMS, Belmont Report, U.S. Common Rule) and were approved by an institutional review board. The data analysis workflow and methods of analysis of SNP arrays (copy number), RNA sequencing and exome sequencing are described in Supplementary Figure 1. PHF10 knock-down and RNA sequencing Established cell lines derived from primary uveal melanomas (Mel202 (22), 92-1 (23) and Mel290 (24) (described in Supplementary Table 1) were subjected to PHF10 knockdown with siRNA (Santa-cruz, sc-95343) or a siRNA control that consisted of scrambled sequence/non-silencing siRNA (Santa-cruz, sc-37007) (SiCtrl). RNA seq was performed with routine methods. In the case of Mel202 and 92-1, RNA was sent to the Centre Nacional d'Anàlisi Genòmica (CNAG, Barcelona, Spain) for processing. In the case of Mel290 (25), 5 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 21, 2019; DOI: 10.1158/1078-0432.CCR-18-3052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RNA was sent to Genewiz (New Jersey, USA; www.genewiz.com). Raw counts were analyzed with DeSeq2 (26). RNA-Seq data from cell lines are available upon request. Migration, Invasion and Adhesion assays:
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