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

Fingerprint

Mutation
GTP-Binding Protein alpha Subunits
Proteins
Focal Adhesion Kinase 1
Encyclopedias
Eye Neoplasms
Phospholipase C beta
BRCA1 Protein
Genome
Neoplasm Metastasis
Genes
Exome
Uveal melanoma
Calcium Signaling
Neoplasm Genes
Protein Subunits
GTP-Binding Proteins
Neoplasms
Learning

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Secondary somatic mutations in g-protein-related pathways and mutation signatures in Uveal melanoma. / Piaggio, Francesca; Tozzo, Veronica; Bernardi, Cinzia; Croce, Michela; Puzone, Roberto; Viaggi, Silvia; Patrone, Serena; Barla, Annalisa; Coviello, Domenico; Jager, Martine J.; Van Der Velden, Pieter A.; Zeschnigk, Michael; Cangelosi, Davide; Eva, Alessandra; Pfeffer, Ulrich; Amaro, Adriana.

In: Cancers, Vol. 11, No. 11, 1688, 11.2019.

Research output: Contribution to journalArticle

Piaggio, F, Tozzo, V, Bernardi, C, Croce, M, Puzone, R, Viaggi, S, Patrone, S, Barla, A, Coviello, D, Jager, MJ, Van Der Velden, PA, 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, vol. 11, no. 11, 1688. https://doi.org/10.3390/cancers11111688
Piaggio, Francesca ; Tozzo, Veronica ; Bernardi, Cinzia ; Croce, Michela ; Puzone, Roberto ; Viaggi, Silvia ; Patrone, Serena ; Barla, Annalisa ; Coviello, Domenico ; Jager, Martine J. ; Van Der Velden, Pieter A. ; Zeschnigk, Michael ; Cangelosi, Davide ; Eva, Alessandra ; Pfeffer, Ulrich ; Amaro, Adriana. / Secondary somatic mutations in g-protein-related pathways and mutation signatures in Uveal melanoma. In: Cancers. 2019 ; Vol. 11, No. 11.
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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.",
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T1 - Secondary somatic mutations in g-protein-related pathways and mutation signatures in Uveal melanoma

AU - Piaggio, Francesca

AU - Tozzo, Veronica

AU - Bernardi, Cinzia

AU - Croce, Michela

AU - Puzone, Roberto

AU - Viaggi, Silvia

AU - Patrone, Serena

AU - Barla, Annalisa

AU - Coviello, Domenico

AU - Jager, Martine J.

AU - Van Der Velden, Pieter A.

AU - Zeschnigk, Michael

AU - Cangelosi, Davide

AU - Eva, Alessandra

AU - Pfeffer, Ulrich

AU - Amaro, Adriana

PY - 2019/11

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N2 - 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.

AB - 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.

KW - Driver mutation

KW - Gene set enrichment

KW - Mutation signature

KW - Tumor evolution

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