TY - JOUR
T1 - Rare, functional, somatic variants in gene families linked to cancer genes
T2 - GPCR signaling as a paradigm
AU - Raimondi, Francesco
AU - Inoue, Asuka
AU - Kadji, Francois M.N.
AU - Shuai, Ni
AU - Gonzalez, Juan Carlos
AU - Singh, Gurdeep
AU - de la Vega, Alicia Alonso
AU - Sotillo, Rocio
AU - Fischer, Bernd
AU - Aoki, Junken
AU - Gutkind, J. Silvio
AU - Russell, Robert B.
N1 - Funding Information:
Funding FR, JCG, GS and RBR are supported by the Cell Networks Excellence initiative of the Germany Research Foundation (DFG). FR was supported by an Alexander Von Humboldt post-doctoral fellowship and a Michael J. Fox Foundation research grant. RBR is part of the DFG SFB/TPR186 Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission, and a member of the BMBF German Network for Bioinfomatics Infrastructure (de.NBI). AI was funded by Japan Science and Technology Agency (JST) Grant Number JPMJPR1331, Japan Agency for Medical Research and Development (AMED) Grant Number JP17gm5910013 and Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 17K08264. JA received funding from AMED Grant Number JP17gm0710001. The authors thank Ayumi Inoue, Naoko Kuroda and Yuko Sugamura (Tohoku University) for plasmid construction and cell culture experiments. We also thank a reviewer for the helpful suggestion to explore the wider set of genes potentially affecting cAMP in cancer.
PY - 2019/9/19
Y1 - 2019/9/19
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-019-0895-2
DO - 10.1038/s41388-019-0895-2
M3 - Article
C2 - 31337866
AN - SCOPUS:85069451026
VL - 38
SP - 6491
EP - 6506
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 38
ER -