The biology of uveal melanoma

Cancer Metastasis Rev DOI 10.1007/s10555-017-9663-3 The biology of uveal melanoma Adriana Amaro 1 & Rosaria Gangemi 2 & Francesca Piaggio 1 & Giovanna Angelini 1 & Gaia Barisione 2 & Silvano Ferrini 2 & Ulrich Pfeffer 1 # The Author(s) 2017. This article is published with open access at Springerlink.com Abstract Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and Adriana Amaro and Rosaria Gangemi equally contributed to the work. * Ulrich Pfeffer 1 Laboratory of Molecular Pathology, Department of Integrated Oncology Therapies, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, L.go Rosanna Benzi 10, 16132 Genoa, Italy 2 Laboratory of Biotherapies, Department of Integrated Oncology Therapies, IRCCS AOU San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment. Keywords G-protein signaling . YAP/TAZ signaling . Immune checkpoint blockers . Targeted therapy . Molecular classification 1 Introduction Uveal melanoma (UM) is a rare disease but the most frequent non-cutaneous melanoma and the most frequent primary cancer of the eye in the adult. In recent years, our understanding of this disease has made a leap forward through the identification of the molecular players likely responsible for tumor initiation and progression. The process of multistep carcinogenesis is now known in considerable detail, perhaps better than for any other neoplasia, and prognosis can be made with utmost precision. This is contrasted by the lack of adjuvant therapy and low efficacy of therapy for metastatic UM, leading to survival rates that have not significantly changed over decades. This review gives a general overview of the current knowledge in the field of UM, incorporating the most relevant findings on the biology of this disease and their implications in clinical management. Reference to recent reviews that give more detailed descriptions is given wherever possible. Cancer Metastasis Rev 2 Clinical features of uveal melanoma 2.2 Etiology 2.1 Epidemiology The etiology of UM is still unclear. UV radiation has clearly been identified as the major risk factor for CM [16], but the role of UV radiation in the development of UM is still under debate [17]. Cornea, lens, and vitreous body absorb almost all wavelengths below 300 nm and much of the spectrum between 300 and 400 nm [18]. However, age-dependent alterations of the vitreous body [19] might alter the absorptive capacity of the latter. The associations between UM risk and blue iris or a generally weakly pigmented phenotype [20, 21] and sun exposure [22] suggest a role for UV radiation in the etiology of UM. A meta-analysis of 133 reports on UVassociated risk factors for UM showed a significant correlation for welding (OR = 2.05; CI 1.20–3.51) but not for outdoor leisure activities (OR = 0.86; CI 0.71–1.04), occupational sunlight exposure (OR = 1.37; CI 0.96–1.96), and latitude of birth (OR = 1.08, CI 0.67–1.74) [23]. If there is a role for UV light in UM etiology, it is certainly by far weaker than that for CM. The etiologic effect of UV radiation for UM is likely too weak to overcome confounding factors such as co-distribution of weakly pigmented skin and iris and latitude, co-occurrence of UV radiation with light of longer wavelengths, and protective, vitamin D-mediated effects of sun exposure [24]. Violet/ blue light, the most energetic form next to UV light, has also been cited as a potential risk factor for UM [25]. Genetic variants on chromosome 15q13.1, close to the genes HERC2 and OCA2 on 15q12 that are involved in the determination of eye color, have been found associated with UM risk [26], and the G proteins GNAQ and GNA11 that are frequently mutated in UM [27, 28] are involved in the determination of skin color in mice [29]. In contrast to inconclusive epidemiological data, molecular data can clearly exclude a typical UV-associated mutational spectrum for UM; in fact, it shows a relatively low mutational load when analyzed by whole exome sequencing and no enrichment for UV-typical C>T transitions at dipyrimidine sites [27, 28, 30–32]. UV-induced mutations in the promoter of the human Telomerase Reverse Transcriptase (TERT) gene occur in approximately 70% of CMs [33, 34] but are rare in UMs [35–37]. Hence, if light has a role in UM carcinogenesis, it certainly acts in a different manner than in CM. Approximately 5% of all melanomas affect the eye, making it the most common site for melanoma development after the skin [1]. The vast majority (85%) of ocular melanomas occur in the uveal tract, which is the vascular layer of the eye (comprising the choroid, the ciliary body, and the iris), and hence are known as UM. Conjunctival melanoma is a rare tumor that develops in the mucous membrane lining the inner surface of the eyelids and the forepart of the eyeball. The clinical and histopathological features of conjunctival and uveal melanomas are clearly different; hence, the two entities should not be confused. Uveal melanoma has molecular affinities with melanocytic tumors of the central nervous system [2] whereas conjunctival melanomas show mutation patterns similar to cutaneous melanoma (CM) [3, 4]. The incidence of UM in the USA is 4.3 per million (4.1– 4.5; 95% confidence interval [CI]) with a prevalence in males (males, 4.9 [4.6–5.2], 95% CI; females, 3.7 [3.5–3.9], 95% CI). Of the cases registered, 97.8% occurred in the white population [5]. There i (...truncated)