Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma.

Francesca Piaggio,Domenico Coviello,Pieter A Van Der Velden,Michael Zeschnigk,Martine J Jager,Veronica Tozzo,Annalisa Barla,Roberto Puzone,Silvia Viaggi,Adriana Amaro,Davide Cangelosi,Alessandra Eva,Ulrich Pfeffer,Cinzia Bernardi,Serena Patrone,Michela Croce

doi:10.3390/cancers11111688

Abstract

Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.

Highlights

Uveal melanoma (UM) is a rare tumor with an incidence of 0.2–0.8/100,000 per year
Two unusual cases from the The Cancer Genome Atlas (TCGA) dataset were included in the analysis: one case with the unusually high number of 222 non-synonymous mutations having R183S mutations in both G-protein subunit alpha Q (GNAQ) and G-protein subunit alpha 11 (GNA11), whereas another has a stop gain mutation in GNAQ
Mutations in GNAQ, GNA11, cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) are considered as potential initiating mutations because they are present in most if not all the cells of the tumors, as the mutations lead to constitutive activation of G-protein/calcium signaling [5,6,7,14] and because they are already present in nevi [23]

Summary

Introduction

Uveal melanoma (UM) is a rare tumor with an incidence of 0.2–0.8/100,000 per year. Median survival after development of clinical metastases is less than a year. Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasispromoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). We tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase. Results: Secondary drivers were significantly enriched in KEGG pathways that contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival

Methods

Results

Conclusion