Oncogenic Mutations inGNAQOccur Early in Uveal Melanoma

Abstract

Purpose Early/initiating oncogenic mutations have been identified for many cancers, but such mutations remain unidentified in uveal melanoma (UM). An extensive search for such mutations was undertaken, focusing on the RAF/MEK/ERK pathway, which is often the target of initiating mutations in other types of cancer. Methods DNA samples from primary UMs were analyzed for mutations in 24 potential oncogenes that affect the RAF/MEK/ERK pathway. For GNAQ, a stimulatory αq G-protein subunit which was recently found to be mutated in uveal melanomas, re-sequencing was expanded to include 67 primary UMs and 22 peripheral blood samples. GNAQ status was analyzed for association with clinical, pathologic, chromosomal, immunohistochemical and transcriptional features. Results Activating mutations at codon 209 were identified in GNAQ in 33/67 (49%) primary UMs, including 2/9 (22%) iris melanomas and 31/58 (54%) posterior UMs. No mutations were found in the other 23 potential oncogenes. GNAQ mutations were not found in normal blood DNA samples. Consistent with GNAQ mutation being an early or initiating event, this mutation was not associated with any clinical, pathologic or molecular features associated with late tumor progression. Conclusions GNAQ mutations occur in about half of UMs, representing the most common known oncogenic mutation in this cancer. The presence of this mutation in tumors at all stages of malignant progression suggests that it is an early event in UM. Mutations in this G-protein provide new insights into UM pathogenesis and could lead to new therapeutic possibilities.

Molecular pathology of uveal melanoma

“…Self-sufficiency in growth signals Gain of cell cycle stimulator-activation of pathways The PI3K-AKT prosurvival pathway is constitutively activated in UM. LOH of the PTEN locus occurs in 76% of UM [17][18][19][20][21] The RAF/MEK/ERK pathway is constitutively activated: activating mutations in GNAQ or GNA11 occur in 480% of UM and can activate the RAF/ MEK/ERK pathway 11,[22][23][24][25][26][27][28] …”

“…11,22,23 However, a systematic interrogation of candidate oncogenes in the MAPK pathway undertaken by several groups was initially disappointing. 24 For example, mutations in KIT and the three RAS family members, which can activate the MAPK pathway, were shown to be exceedingly rare in UM. 23,[63][64][65][66]92 Similarly, BRAF mutations, well described in cutaneous melanomas, have been reported in choroidal melanomas, 67 but are very rare.…”

“…22,23,65,68,93 Further, mutations in the other two members of the RAF family, ARAF and CRAF, are not found in UM. 24 Guanine nucleotide-binding protein G(q) subunit (GNAQ, or G-alpha-q) and GNA11 mutations This puzzle concerning the MAPK pathway, and the mechanisms by which it was constitutively activated, persisted until the recent discovery of mutations in GNAQ in almost half of UM. 24,25 GNAQ is one of a subfamily of G protein a subunit encoding genes, comprising GNAQ, GNA11, GNA14 and GNA15/16.…”

Targeted Therapy for Cutaneous Melanoma: Beyond BRAF...

“…In addition, the discovery that ~80% of uveal melanomas have hotspot mutations in genes (GNαQ, GNα11) that regulate the activity of G-protein coupled receptors has led to new clinical trials for patients with that disease as well. [68][69][70] Based on the lessons learned in the development of targeted therapies for BRAF V600 mutations, many clinical studies in melanoma patients include planned analyses to identify molecular features that predict sensitivity or resistance. As effective strategies are identified, there is also strong evidence to support the collection of biopsies from progressing lesions to rapidly identify and develop rational combinatorial strategies.…”

Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

“…These mutations are mutually exclusive, affecting 46% and 35% of UM cases respectively [11][12] [13]. Oncogenic signaling as a result of GNAQ/11 mutations is reported to hyperactivate the PLCβ/PKC/MAPK pathway (14][15] [16].…”