Dataset Information

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

ABSTRACT: Mutations of the Gα-proteins GNAQ and GNA11 are found in 85-90% of uveal melanomas (UMs). We analyzed the association of GNAQ and GNA11 mutations with disease-specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. Our analysis showed a shorter disease-specific survival of GNA11 mutated cases as compared to those carrying a GNAQ mutation (median months: 26.97 [95% CI 25.02-37.08], vs not reached, p=0.058; HR=1.97 [95%CI 1.12-3.46], p=0.02). The GNA11 mutation was associated with expression alterations of the BRCA1-associated protein 1 (BAP1; p=0.0005), chr3 monosomy (p=0.0002), chr8q amplification (p=0.038), the combination of the latter two (p=0.0002), and, inversely, with chr6p amplification (p=0.003). We used tandem-affinity-purification and mass spectrometry to show that the two G-proteins have different protein interaction partners. The Tet Methylcytosine Dioxygenase 2, TET2, a protein that is involved in DNA-demethylation, physically interacts with GNAQ but not with GNA11 as confirmed by immunoprecipitation analyses. High risk UM shows a clearly different DNA-methylation pattern and different control of DNA-methylation by the two G-proteins might, at least in part, explain the different association with UM progression.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Martina Bartolucci

LAB HEAD: Andrea Petretto

PROVIDER: PXD030217 | Pride | 2022-06-22

REPOSITORIES: Pride

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Publications

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.

Piaggio Francesca F Croce Michela M Reggiani Francesco F Monti Paola P Bernardi Cinzia C Ambrosio Marianna M Banelli Barbara B Dogrusöz Mehmet M Jockers Ralf R Bordo Domenico D Puzone Roberto R Viaggi Silvia S Coviello Domenico D Lanza Francesco B FB Bartolucci Martina M Petretto Andrea A Mosci Carlo C Gangemi Rosaria R van der Velden Pieter A PA Jager Martine J MJ Pfeffer Ulrich U Amaro Adriana A

European journal of cancer (Oxford, England : 1990) 20220514

<h4>Background and aim of the study</h4>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.<h4>Methods</h4>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-purif ...[more]

PMID: 35580369

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Project description:Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1,169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranked regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (p=0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR=1.061, 95% CI: 1.032-1.090), and the sensitivity (AUC = 0.638, 95% CI: 0.586-0.690), (Males=0.675, Females=0.609), was better than of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals that stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM, and suggest a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM. Five pools of DNA samples consist of 710 T2DM patients and 459 control individuals were analyzed for average methylation levels at 1,461,753 DNA genomic fragments containing 3,359,645 CpG methylation sites using four SNP arrays for each sample, two 'genomic' (before treatment) replicates and two MSRE (treatment with a cocktail of five methyl-sensitive-restriction-enzyme) replicates. The analysis was done using the Affymetrix SNP 6.0 array.

Dataset Information

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

Publications

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.

Similar Datasets

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