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

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.

G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

“…These include mutations localized to the DRY motif, which mediates the inactive conformation of class A GPCRs, with particular emphasis on recurrent mutations in DRY arginine, in addition to the nPxxY motif, both of which are critical regulators of GPCR activation. Mutations in these positions show statistically significant mutual exclusivity between motifs, as well as with activating hotspot mutations in the Gα subunit further supporting the functional significance of these structure‐based predictions [47]. DRY arginine mutations are also mutually exclusive with many common mutant oncogenes that are downstream of GPCR‐mediated signalling cascades, including AKT E17K, PIK3CA E545K, and JAK2 V617F [47].…”

“…Strikingly, our recent study found that there is widespread activation of the Gαs pathway across a large proportion of cancer types in TCGA with a remarkable enrichment in cancers of the gastrointestinal tract 47 . Consistent with this, the Gαs subfamily is mutated in 5.24% of colorectal, 5.03% of pancreatic and 5.96% of stomach adenocarcinomas ( Table 1, Table S5).…”

“…Across TCGA PanCancer studies, GNA13 appears to have a potential hotspot mutation at R200, although it has not been formally tested and annotated as such by OncoKB 197 (Figure 2D). This cluster of mutations appears exclusively in bladder urothelial carcinomas, where GNA13 is significantly mutated (MutSig2CV q-value = 0.003); however, the function is currently unknown 47 (Table S3). G12/13 has been well-studied in the context of DLBCL where it is mutated in 7.32% of patients in TCGA ( Table 1, Table S5).…”

Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy

“…A complicating factor is that most GPCRs do not harbor hotspot mutations, meaning that mutations in each GPCR do not occur with high frequency in a single or limited numbers of codons, and in addition, each tumor exhibits a different repertoire of mutated GPCRs. To address this daunting question, we have recently developed new bioinformatics approaches analyzing GPCR mutations in the context of multiple sequence alignments (MSA) defining the conserved seven-transmembrane (7TM) domain, as well as considering 3D structures and interaction partners (241). We have used this approach to model the most significantly mutated GPCRs (Table S2A).…”

“…Although the functional impact of these alterations may need to be investigated for each GPCR, our recent computational analysis of cancer genomes indicates that most G␣ i -linked GPCRs exhibit DRY mutations that are inhibitory in nature (inhibit function), which typically occur mutually exclusively with GNAS9-activating mutations (241). This suggests the exciting possibility that mutations in G␣ i -GPCRs may mimic GNAS mutants leading to higher cAMP activity to drive tumorigenesis (241).…”