The genetics of uveal melanoma: an emerging framework for targeted therapy

Abstract

Uveal melanoma is the second most common form of melanoma and the most common primary intraocular malignancy. Until recently, very little was known about the genetics of this aggressive cancer. Mutations in oncogenes and tumor suppressors that are common in other cancers are conspicuously absent in uveal melanoma. In recent years, however, uveal melanoma has begun to yield its secrets, and a fascinating picture is emerging of how it develops and progresses. Mutations in the G(q) alpha subunits, encoded by GNAQ and GNA11, appear to be early or perhaps initiating events that require further mutations for malignant transformation. On the other hand, mutations in the BRCA1-associated protein-1 (BAP1) appear to occur later and demarcate a molecular brink beyond which metastasis becomes highly likely. BAP1 mutations can also occur in the germline, leading to a distinctive cancer predisposition syndrome. These mutations appear to be key events that provide the potential for targeted therapy. This article will review the genetic findings in uveal melanoma over the past two decades and suggest important areas for future work.

Figure 1

Common chromosomal gains and losses in cutaneous and uveal melanomas. This represents a summary of data published by Hoglund and colleagues (Hoglund et al., 2004). Data are presented for all chromosomal arms in which the indicated alteration was present in at least 20% of either cutaneous or uveal melanomas. (−) indicates loss and (+) indicates gain of the indicated chromosomal arm of whole chromosome.

Figure 2

Summary of the combinations of alterations observed on chromosomal arms 8p and 8q in 240 primary uveal melanomas. These data were compiled from 10 published studies that used karyotype analysis, FISH or CGH (Aalto et al., 2001; Hughes et al., 2005; Kilic et al., 2006; Naus et al., 2001; Prescher et al., 1995; Sisley et al., 1997; Speicher et al., 1994; Tschentscher et al., 2000; White et al., 1998; Wiltshire et al., 1993).

Figure 3

Summary of major molecular events in uveal melanoma progression. The earliest known and perhaps initiating event is an activating mutation in GNAQ or GNA11, presumably in a normal uveal melanocyte (MC), which may function primarily to trigger inappropriate cell cycle re-entry through activation of the MAPK and perhaps other pathways. Usually the mutant cell clone does not progress to melanoma, but rather undergoes senescence resulting in a nevus, or is eliminated by apoptosis or immune surveillance (small black spheres). Less than one in 8000 nevi progress beyond this stage (Singh et al., 2005b). The rare tumor that progresses does so along one of the two pathways characterized by distinct gene expression profiles (GEP). The GEPs of normal uveal melanocytes and nevi are very similar to that of class 1 uveal melanomas (blue spheres) (Chang et al., 2008), which have a low risk of metastasis (small purple sphere). Melanomas that acquire the class 2 GEP (class 2 MM) have a very high risk of metastasis (large purple sphere). Class 1 tumors often exhibit 6p gain and 8q gain, but have less overall aneuploidy than class 2 tumors, which often exhibit 1p loss, 8p loss, and 8q gain. 8q gain is more common in class 2 tumors, but is also seen in class 1 tumors, so this may be a late event (Parrella et al., 1999). The class 2 GEP is strongly associated with mutation of BAP1, located at 3p21, and loss of the other copy of chromosome 3, suggesting that bi-allelic loss of BAP1 is a key step in uveal metastasis (Harbour et al., 2010). Metastatic tumors (purple spheres) have a distinct gene expression profile that is more similar to that of class 2 than that of class 1 primary tumors (author’s unpublished data). MC, melanocyte; MM, malignant melanoma; Met, metastasis.