Rare, functional, somatic variants in gene families linked to cancer genes: GPCR signaling as a paradigm
| Autor: | Robert B. Russell, Rocio Sotillo, Francois Marie Ngako Kadji, Ni Shuai, Asuka Inoue, Bernd Fischer, Junken Aoki, Gurdeep Singh, Alicia Alonso de la Vega, Francesco Raimondi, J. Silvio Gutkind, Juan Carlos Gonzalez |
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| Přispěvatelé: | Raimondi, F., Inoue, A., Kadji, F. M. N., Shuai, N., Gonzalez, J. -C., Singh, G., de la Vega, A. A., Sotillo, R., Fischer, B., Aoki, J., Gutkind, J. S., Russell, R. B. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Models Molecular Cancer Research Cell signaling Gs alpha subunit Biology Article Receptors G-Protein-Coupled 03 medical and health sciences 0302 clinical medicine Gene Frequency Neoplasms Genetics medicine GNAS complex locus Cancer genomics Chromogranins GTP-Binding Protein alpha Subunits Gs Gene family Humans Gene Regulatory Networks Genes Tumor Suppressor Molecular Biology Gene HEK 293 cells Cancer Computational Biology Epistasis Genetic Oncogenes medicine.disease Survival Analysis 030104 developmental biology HEK293 Cells 030220 oncology & carcinogenesis Multigene Family Mutation biology.protein Epistasis Cell signalling Signal Transduction Transcription Factors |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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