The finding of
GNAQ mutations in half of UMs raises the exciting possibility that other important oncogene mutations will be found in the other UMs. The role of GNAQ in activating the RAF/MEK/ERK pathway would suggest that future searches for early oncogenic mutations in UM should focus on genes in this pathway. We screened 23 other potential oncogenes in this pathway. Members of the RAS superfamily of small GTPases are commonly mutated in cutaneous melanoma and other cancers, so we resequenced several members of this family (
DIRAS2,
REM1,
GEM,
RAB2A,
RAB22A, and
RAB23), as well as positive effectors of RAS signaling (
DIRAS2,
RAPGEF1, and
RASIP1), the RAS homolog GTPase activating protein
ARHGAP1, and the serine/threonine protein kinase
PAK7, which is an effector of RAS homolog RAC/CDC42 GTPases.
HRAS,
KRAS, and
NRAS previously have been shown to be free of mutations in UM,
6 7 8 and not analyzed in this study. Similarly,
BRAF is frequently mutated in cutaneous melanoma and other cancers, but not in UM,
6 7 9 31 so we extended our resequencing to the other RAF family members,
ARAF and
RAF1. The PI3K pathway is activated in UMs
38 and can activate MEK/ERK.
30 Thus, we analyzed several members of the PI3K pathway, including
PTPN11,
PTK2,
PTK6,
PIK3R1 (the regulatory subunit of PI3K), and
PIP5KL1. We also analyzed
GRM1 and
EDG5, which are G-protein coupled receptors that interact with GNAQ and are associated with melanoma phenotypes.
39 40 41 Even though our mutational screen revealed no additional oncogenic mutations, this screening was valuable in narrowing the search for oncogenic mutations in future studies. To this list can be added the
GNAQ-associated genes
GNA12-15,
GNAS, and
ENDRB, which were previously analyzed and found to harbor no mutations in UM.
16 Future studies should continue to focus on screening for mutations in members of this pathway.