Genome-wide association and population-tailored polygenic risk for Parkinson's disease in Taiwan.

Uveal melanoma (UM) is the most commonly encountered primary intraocular cancer arising in adults [] and represents 3–5% of all reported melanomas []. The most common sites for development of UM are choroidal melanocytes (85–90%), ciliary body (5–8%) and iris tissue (3–5%) []. From an epidemiology standpoint, males have a reported incidence 30% greater than females []. According to Krantz. B. et al., the median age of diagnosis for UM is around 62 years with the peak range between 70 and 79 years old []. The reported age range for UM is similar to cutaneous melanoma (greatest reported incidence >70 years old and greater in males) []. However, from a clinical and genetic standpoint, UM is very different from cutaneous melanoma (CM). UM cells characteristically carry activating mutations in G-protein-coupled receptor (GPCR) signaling such as GNAQ and GNA11 component mutations in the alpha subunits of guanine nucleotide-binding proteins (G-proteins) Gα and Gα []. GNAQ and GNA11 gene mutations occur in a mutually exclusive manner in 93% of UM tumors [,] with GNAQ mutations detected in ~50% of UM tumors and GNA11 in ~43% of tumors []. These gene mutations effectively switch on the GTPase activity of G-proteins by turning on from an inactive state (bonded with guanosine diphosphate GDP) to an active state (bonded with guanosine triphosphate GTP) []. An important genetic event in the progression of UM to metastasis is inactivating somatic mutations in genes encoding the BRCA-1-associated protein 1 (BAP1) [,,]. According to Singh N. et al., uveal melanoma is the most frequent tumor associated with BAP1 tumor predisposition syndrome (BAP1-TPDS) and furthermore can also manifest as bilateral primary uveal melanoma in BAP1-TPDS []. Mutations in BAP1 (80% of aggressive UM forms []) are associated with poor prognostic factors []. Other less common mutations than BAP1-reported mutations are Splicing Factor 3b Subunit 1 (SF3B1, exon 14, 26% of UM cases []) and Eukaryotic translation initiation factor 1A X-linked (EIF1AX, exons 1 and 2, 19% of UM cases []) []. Mutations in BAP1, SF3B1, EIF1AX are almost mutually exclusive with each other and may represent alternative downstream molecular events during tumor progression []. From a clinical standpoint, treatment of primary UM via surgery, radiotherapy or brachytherapy is often successful for the primary tumor; however, up to half of patients develop distant metastases [] years after the original tumor was successfully treated []. UM characteristically presents a genetic liver-metastasis tropism which has been attributed by several authors to the tumoral expression of chemokine receptor 4 (CXCR4) [,] and C-C Chemokine Receptor Type 7 CCR7 []. Liver parenchyma presents high concentrations of CXCL12, the chemokine ligand for CXCR4 [], while CCR7, also found in cutaneous melanoma, binds to the ligand CCL21 expressed in lymph nodes []. Overall reported metastatic rates by Longhitano L. et al. are 89% for the liver (84% of BAP1-mutated patients), 29% for the lung and 17% for bone metastases [], with predicted survival at 15% upon 5 years []. Despite continuous advancement and research, the risk of metastasis remains high for uveal melanoma [].