Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and GNA11 Mutations.

Abstract

Purpose:

The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM). However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM.

Methods:

Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM. Activation of the MAPK pathway and other potential downstream signals was assessed by immunohistochemistry and/or Western blot analysis. Potential downstream signaling of mutant and wild type GNAQ/11 was studied by transient transfection assay in nonmutant cell lines.

Results:

Somatic mutations in GNAQ/11 were observed in 35/42 (83.3%) of primary UM. Tumors with GNAQ/11 mutations showed variations in the activation of ERK1/2 with significant tumor heterogeneity. Weak and undetectable ERK1/2 activation was observed in 4/35 (11.4%) and 8/35 (22.9%) of the GNAQ/11 mutant UM, respectively. Tumor heterogeneity of GNAQ/11 mutations was also observed in a subset of tumors.

Conclusions:

Our results indicate that there is marked variation in MAPK activation in UM with GNAQ/11 mutations. Thus, GNAQ/11 mutational status is not a sufficient biomarker to adequately predict UM patient responses to single-agent selective MEK inhibitor therapy.

• Authors: Getachew Boru, Colleen M Cebulla, Klarke M Sample, James B Massengill, Frederick H Davidorf, Mohamed H Abdel-Rahman
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 60 Issue 7 Pg. 2474-2480 (06 03 2019) ISSN: 1552-5783 [Electronic] United States
• PMID: 31173078 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GNA11 protein, human
• GNAQ protein, human
• GTP-Binding Protein alpha Subunits
• Mitogen-Activated Protein Kinases
• GTP-Binding Protein alpha Subunits, Gq-G11

Topics

• Blotting, Western
• Cell Line, Tumor
• Cohort Studies
• DNA Mutational Analysis
• GTP-Binding Protein alpha Subunits (genetics)
• GTP-Binding Protein alpha Subunits, Gq-G11 (genetics)
• Humans
• Immunohistochemistry
• Melanoma (enzymology, genetics)
• Mitogen-Activated Protein Kinases (metabolism)
• Mutation
• Plasmids
• Polymorphism, Restriction Fragment Length
• Sequence Analysis, DNA
• Signal Transduction
• Transfection
• Uveal Neoplasms (enzymology, genetics)