The biology of uveal melanoma
The biology of uveal melanoma
Adriana Amaro 0 1
Rosaria Gangemi 0 1
Francesca Piaggio 0 1
Giovanna Angelini 0 1
Gaia Barisione 0 1
Silvano Ferrini 0 1
Ulrich Pfeffer 0 1
0 Laboratory of Biotherapies, Department of Integrated Oncology Therapies, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro , Genoa , Italy
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
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 probab l y a l s o c o n t r i b u t e s t o U M d e v e l o p m e n t a n d Ulrich Pfeffer 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.
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.
2 Clinical features of uveal melanoma
2.2 Etiology
2.1 Epidemiology
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 is a strong difference in the incidence for
different ethnic groups: the annual age-adjusted incidence is
0.31 for Afro-Americans, 0.38 for Asians, 1.67 for Hispanics,
and 6.02 for non-Hispanic whites [6], yet prognosis does not
differ for ethnic groups [7]. The European Cancer
Registrybased study on survival and care of cancer patients
(EUROCARE) for the years 1983–1994 reported similar
incidence rates with a characteristic increase from south to
north, from <2 per million in Spain and Southern Italy to >8
per million in Norway and Denmark [8]. This is consistent (...truncated)