In uveal melanoma Gα-protein GNA11 mutations convey a shorter disease-specific survival and are more strongly associated with loss of BAP1 and chromosomal alterations than Gα-protein GNAQ mutations.

Autor: Piaggio F; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Croce M; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Reggiani F; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Monti P; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Bernardi C; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Ambrosio M; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Banelli B; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Dogrusöz M; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands., Jockers R; Université de Paris, Institut Cochin, INSERM, CNRS, F-75014 PARIS, France., Bordo D; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Puzone R; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Viaggi S; Laboratorio Genetica Umana, IRCCS Istituto Giannina Gaslini, IRCCS Giannina Gaslini Institute Genova, Italy; Department of Earth Sciences, Environment, and Life, Università Degli Studi di Genova, Genova, Italy., Coviello D; Laboratorio Genetica Umana, IRCCS Istituto Giannina Gaslini, IRCCS Giannina Gaslini Institute Genova, Italy., Lanza FB; Ocular Oncology Service, Department of Surgical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Venezian 1, 20133 Milan, Italy., Bartolucci M; Core Facilities-Clinical Proteomics and Metabolomics, IRCCS Giannina Gaslini Institute, Genova, Italy., Petretto A; Core Facilities-Clinical Proteomics and Metabolomics, IRCCS Giannina Gaslini Institute, Genova, Italy., Mosci C; Ente Ospedaliero Galliera, Genova, Italy., Gangemi R; IRCCS Ospedale Policlinico San Martino, Genova, Italy., van der Velden PA; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands., Jager MJ; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands., Pfeffer U; IRCCS Ospedale Policlinico San Martino, Genova, Italy. Electronic address: ulrich.pfeffer@hsanmartino.it., Amaro A; IRCCS Ospedale Policlinico San Martino, Genova, Italy.
Jazyk: angličtina
Zdroj: European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2022 Jul; Vol. 170, pp. 27-41. Date of Electronic Publication: 2022 May 14.
DOI: 10.1016/j.ejca.2022.04.013
Abstrakt: Background and Aim of the Study: Mutations in the Gα-genes GNAQ and GNA11 are found in 85-90% of uveal melanomas (UM). Aim of the study is to understand whether the mutations in both genes differentially affect tumor characteristics and outcome and if so, to identify potential mechanisms.
Methods: We analyzed the association between GNAQ and GNA11 mutations with disease-specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. We used tandem-affinity-purification, mass spectrometry and immunoprecipitation to identify protein interaction partners of the two G-proteins and analyzed their impact on DNA-methylation.
Results: GNA11 mutation was associated with: i) an increased frequency of loss of BRCA1-associated protein 1 (BAP1) expression (p = 0.0005), ii) monosomy of chromosome 3 (p < 0.001), iii) amplification of chr8q (p = 0.038), iv) the combination of the latter two (p = 0.0002), and inversely with v) chr6p gain (p = 0.003). Our analysis also showed a shorter disease-specific survival of GNA11-mutated cases as compared to those carrying a GNAQ mutation (HR = 1.97 [95%CI 1.12-3.46], p = 0.02). GNAQ and GNA11 encoded G-proteins have different protein interaction partners. Specifically, the Tet Methylcytosine Dioxygenase 2 (TET2), a protein that is involved in DNA demethylation, physically interacts with the GNAQ protein but not with GNA11, as confirmed by immunoprecipitation analyses. High-risk UM cases show a clearly different DNA-methylation pattern, suggesting that a different regulation of DNA methylation by the two G-proteins might convey a different risk of progression.
Conclusions: GNA11 mutated uveal melanoma has worse prognosis and is associated with high risk cytogenetic, mutational and molecular tumor characteristics that might be determined at least in part by differential DNA-methylation.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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