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Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project

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Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project cancers Review Molecular Characteristics of Uveal Melanoma: Insights from the Cancer Genome Atlas (TCGA) Project Mathieu F. Bakhoum 1 and Bita Esmaeli 2,* 1 Shiley Eye Institute, Jacobs Retina Center, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92093, USA 2 Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA * Correspondence: [email protected]; Tel.: +1-713-792-4457; Fax: +1-713-794-4662 Received: 6 July 2019; Accepted: 22 July 2019; Published: 27 July 2019 Abstract: The Cancer Genome Atlas (TCGA) uveal melanoma project was a comprehensive multi-platform deep molecular investigation of 80 uveal melanoma primary tissue samples supported by the National Cancer Institute. In addition to identification of important mutations for the first time, it identified four different clusters (subgroups) of patients paralleling prognosis. The findings of the TCGA marker paper are summarized in this review manuscript and other investigations that have stemmed from the findings of the TCGA project are reviewed. Keywords: uveal melanoma; TCGA; whole exome sequencing; RNA seq; methylation; immune infiltrates 1. Background and Historical Perspective Uveal melanoma (UM), the most common primary intraocular tumor in adults, is characterized by marked variability in its ability to metastasize. Up to half the patients with UM develop distant metastases, most commonly to the liver [1–3]. Once metastasis is clinically detected, the median survival is less than 12 months [2,4]. The Collaborative Ocular Melanoma Study (COMS), a large multi-center prospective trial, showed that local radiotherapy or enucleation are equally effective in achieving local control of the primary tumor with no difference in incidence of metastatic disease. Despite achieving local control of the primary tumor, overall survival rates have remained constant over the last four decades [5]. It is thought that micro-metastases may have already occurred by the time of enucleation, and that the chance of developing clinically significant metastases largely depends on the genetic underpinnings of the primary tumor. This variable metastatic proclivity was first demonstrated by Callender, who noted that UM with a predominant epithelioid cellular morphology, characterized by large nuclei, have worse prognosis than those with a predominantly spindle morphology [6,7]. Recurrent cytogenetic abnormalities have also been noted in UM and were found to correlate with metastatic tendencies. For instance, loss of chromosome 3 (monosomy 3) and gain of chromosome 8q are strong predictors of metastasis, whereas gain of 6p confers a better prognosis [8–13]. These non-random karyotypic aberrancies indicated that tumors with worse prognosis may have a unique molecular profile. In fact, UM with monosomy 3 were found to have a distinct gene expression profile [14]. This led to the development of a clinical prognostic test which has the ability to stratify tumors, solely based on gene expression patterns, into two major classes, with strikingly different survival outcomes [15,16]. The Cancer Genome Atlas (TCGA) project was a multi-center institutional effort, supported by the National Institute of Health, with the aim of providing a comprehensive genetic analysis of different cancers and establishing correlations with clinical outcomes. Eighty primary UM, with their associated Cancers 2019, 11, 1061; doi:10.3390/cancers11081061 www.mdpi.com/journal/cancers Cancers 2019, 11, x FOR PEER REVIEW 2 of 11 different cancers and establishing correlations with clinical outcomes. Eighty primary UM, with their associated clinicopathologic data, were included in a Rare Tumor Project of TCGA [17]. Mutations, genomic copy number alterations, transcriptomic and methylation profiles were analyzed for all eighty specimens. Additionally, whole genome sequencing was performed on fifty specimens and Cancers 2019, 11, 1061 2 of 11 reverse-phase protein array (RPPA) was performed on eleven specimens. This review focuses on the main findings and analysis generated from TCGA, which was reported by Robertson et al. [17]. clinicopathologic data, were included in a Rare Tumor Project of TCGA [17]. Mutations, genomic copy 2. Mutationalnumber alterations, Landscape transcriptomic and methylation profiles were analyzed for all eighty specimens. Additionally, whole genome sequencing was performed on fifty specimens and reverse-phase protein arrayUnlike (RPPA) cutaneous was performed melanoma, on the eleven mutational specimens. burden This in review UM is focuses low. The on median the main somatic findings mutation and densityanalysis in the generated TCGA fromcohort TCGA, was whichfound was to reportedbe 1.1 per by RobertsonMb in UM et al.versus [17]. 18 per Mb in cutaneous melanoma [17,18]. There was no evidence of UV radiation mutational signature in UM consistent 2. Mutational Landscape with prior observations [19]. Nine genes were significantly mutated in the cohort—GNAQ, GNA11, BAP1, SF3B1Unlike, EIF1AX cutaneous, CYSLTR2 melanoma,, theSRSF2 mutational, MAPKAPK5 burden in, UMand isPLCB4 low. The [17], median as somaticshown mutationin Table 1. Mutationsdensity in in alpha the TCGA G-protein cohort subunits, was found GNAQ to be and 1.1 GNA11 per Mb, inwere UM found versus in 18 92.5% per Mb of the in cutaneous samples, in a mutuallymelanoma exclusive [17,18 pattern]. There consistent was no evidence with ofprior UV radiationobservations mutational [17,20–22]. signature Tumors in UM that consistent did not with harbor theseprior mutations observations were [found19]. Nine to geneshave mutations were significantly in CYSLTR2 mutated, a in G-protein-coupled the cohort—GNAQ ,receptor,GNA11, BAP1 in 4%, of SF3B1, EIF1AX, CYSLTR2, SRSF2, MAPKAPK5, and PLCB4 [17], as shown in Table1. Mutations in alpha samples and in PLCB4, a downstream effector of GNAQ signaling in 2.5% of samples [17,19,23], G-protein subunits, GNAQ and GNA11, were found in 92.5% of the samples, in a mutually exclusive highlighting the involvement of G-protein signaling in the biology of uveal melanoma. There was no pattern consistent with prior observations [17,20–22]. Tumors that did not harbor these mutations were differencefound toin haveoutcomes mutations (overall in CYSLTR2 survival, a G-protein-coupledor metastasis) between receptor, these in 4% mutations. of samples andThis in suggestsPLCB4, a that activatingdownstream mutations effector in of GNAQ/11GNAQ signaling are an in 2.5%early of event samples in [17 UM,19, 23oncogenesis.], highlighting In the fact, involvement mutations of in GNAQ/11G-protein were signaling found in themost biology benign of uvealnevi [20,24,25]. melanoma. In There vitro was studies no diff erencehave supported in outcomes the (overall potential role ofsurvival activating or metastasis) GNAQ/11 between mutations these mutations.in cellular This growth. suggests GNAQ/11.Q209L that activating mutations mutation in wasGNAQ shown/11 to activateare anYes-associated early event in protein UM oncogenesis. (YAP) and Intranscriptional fact, mutations coactivator in GNAQ/11 withwere PDZ-binding found in most motif benign (TAZ), two transcriptionalnevi [20,24,25]. In enhancers vitro studies with have oncogenic supported potentia the potentiall [26–28]. role Ectopic of activating expressionGNAQ /11of mutationsthe activating mutationin cellular GNAQ/11.Q209L growth. GNAQ in/ 11.Q209Lzebrafishmutation along with was inactivation shown to activate of the Yes-associated tumor suppressor protein TP53 (YAP led) to tumorand formation transcriptional [29,30], coactivator while expression with PDZ-binding of GNAQ/11.Q209L motif (TAZ), twoalone transcriptional led to profound enhancers pigmentation with oncogenic potential [26–28]. Ectopic expression of the activating mutation GNAQ/11.Q209L in zebrafish defects without oncogenic transformation, supporting the hypothesis that the activating GNAQ/11 along with inactivation of the tumor suppressor TP53 led to tumor formation [29,30], while expression mutations are precursor events requiring a ‘second hit’ in order to lead to malignant transformation, of GNAQ/11.Q209L alone led to profound pigmentation defects without oncogenic transformation, as shownsupporting in Figure the hypothesis1 [31]. that the activating GNAQ/11 mutations are precursor events requiring a ‘second hit’ in order to lead to malignant transformation, as shown in Figure1[31]. Figure 1. Two layers of mutations in uveal melanoma (UM). Mutations in genes involved in G-protein Figuresignaling 1. Two are layers present of in 98%mutation of sampless in inuveal a nearly melanoma mutually exclusive (UM). Mutations manner. They in are genes also present involved in G-proteinin benign choroidalsignaling nevi are and present are therefore in 98% thought of samples to occur in in a thenearly earlier mutually stages of tumorexclusive formation. manner. A second layer of mutations occurs in EIF1AX, SF3B1, SRSF2, and BAP1. They are found in 66% of They are also present in benign choroidal nevi and are therefore thought to occur in the samples in a nearly mutually exclusive manner as well. These mutations confer different prognoses. earlier stages of tumor formation. A second layer of mutations occurs in EIF1AX, SF3B1, SRSF2,A second and BAP1. layer They of mutations are found consist in 66% of of mutations samples in inSF3B1 a nearly, EIF1AX mutually, BAP1 exclusive, and were manner found inas awell. nearly These
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