Rare, functional, somatic variants in gene families linked to cancer genes: GPCR signaling as a paradigm

Oncogene. 2019 Sep;38(38):6491-6506. doi: 10.1038/s41388-019-0895-2. Epub 2019 Jul 23.


Oncodriver genes are usually identified when mutations recur in multiple tumours. Different drivers often converge in the activation or repression of key cancer-relevant pathways. However, as many pathways contain multiple members of the same gene family, individual mutations might be overlooked, as each family member would necessarily have a lower mutation frequency and thus not identified as significant in any one-gene-at-a-time analysis. Here, we looked for mutated, functional sequence positions in gene families that were mutually exclusive (in patients) with another gene in the same pathway, which identified both known and new candidate oncodrivers. For instance, many inactivating mutations in multiple G-protein (particularly Gi/o) coupled receptors, are mutually exclusive with Gαs oncogenic activating mutations, both of which ultimately enhance cAMP signalling. By integrating transcriptomics and interaction data, we show that the Gs pathway is upregulated in multiple cancer types, even those lacking known GNAS activating mutations. This suggests that cancer cells may develop alternative strategies to activate adenylate cyclase signalling in multiple cancer types. Our study provides a mechanistic interpretation for several rare somatic mutations in multi-gene oncodrivers, and offers possible explanations for known and potential off-label cancer treatments, suggesting new therapeutic opportunities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromogranins / genetics
  • Computational Biology
  • Epistasis, Genetic
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Gene Frequency
  • Gene Regulatory Networks / physiology
  • Genes, Tumor Suppressor
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Multigene Family / genetics
  • Mutation* / physiology
  • Neoplasms / genetics*
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Oncogenes / genetics*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / genetics
  • Survival Analysis
  • Transcription Factors / genetics


  • Chromogranins
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs