Secondary somatic mutations in g-protein-related pathways and mutation signatures in Uveal melanoma

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number1688
JournalCancers
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2019

Keywords

  • Driver mutation
  • Gene set enrichment
  • Mutation signature
  • Tumor evolution

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Piaggio, F., Tozzo, V., Bernardi, C., Croce, M., Puzone, R., Viaggi, S., Patrone, S., Barla, A., Coviello, D., Jager, M. J., Van Der Velden, P. A., Zeschnigk, M., Cangelosi, D., Eva, A., Pfeffer, U., & Amaro, A. (2019). Secondary somatic mutations in g-protein-related pathways and mutation signatures in Uveal melanoma. Cancers, 11(11), [1688]. https://doi.org/10.3390/cancers11111688