Abstract
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.
Highlights
These authors contributed : Francesco Raimondi, Asuka InoueDeceased Bernd FischerLead contact: Francesco Raimondi
Understanding the role played by somatic mutations in cancer is critical for the interpretation of large datasets from high-throughput sequencing projects and the development of personalized therapies
Previous studies used protein family evolutionary relationships to highlight positions significantly affected by somatic mutations [16] and suggested that sparse mutations affecting equivalent domain positions in known drivers might display similar downstream consequences [16]
Summary
Even when an oncodriver role is well established, it remains difficult to discriminate driver from passenger mutations, especially when they are rare [6] This task is more daunting when sparse somatic mutations affect genes not previously linked to cancer by standard approaches based on positive selection. The phosphoinositide 3-kinase (PI3K) pathway, shows great redundancy in that downstream target PI3Ks can be activated by many upstream signals transduced by tyrosine kinases and G-protein coupled receptors [13] Instances of this multi-gene oncodriver phenomenon would often be overlooked as mutations in multiple upstream genes necessarily have lower frequencies, and would not be identified as statistically significant in any one-gene-at-a-time analysis. We identify several instances of this phenomenon, involving both oncogenes and tumor suppressors, including sparsely mutated, genes not previously linked to cancer
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