Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

Abstract

G protein-coupled receptors (GPCRs) form the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used an aggregated dataset of mutations found in cancer patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 Genomes project. While the location of these mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment was observed in cancer patients among conserved residues in GPCRs such as the 'DRY' motif. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). The validity of our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, and we identified novel GPCRs that had not been directly linked to cancer before such as the P2Y Receptor 10 (P2RY10). As a proof of concept, we projected the structurally investigated mutations in the crystal structure of the C-C Chemokine (CCR) 5 receptor, one of the high-ranking GPCRs previously linked to cancer. Several positions were pinpointed that relate to either structural integrity or endogenous and synthetic ligand binding, providing a rationale to their mechanism of influence in cancer. In conclusion, this study identifies a list of GPCRs that are prioritized for experimental follow up characterization to elucidate their role in cancer. The computational approach here described can be adapted to investigate the roles in cancer of any protein family.

Impact of Cancer-Associated Mutations in CC Chemokine Receptor 2 on Receptor Function and Antagonism

“…Therefore, it is not surprising that P302L 7.50 and P302R 7.50 mutants showed a loss of receptor activation, as the receptor is no longer able to complete this movement. Noteworthy is that mutations in highly conserved positions of TM regions, including 6.50 and 7.50, rank among the most frequent in the GDC and 1000 genomes datasets, as shown recently by Bongers et al [36].…”

Cancer-Associated Mutations of the Adenosine A2A Receptor Have Diverse Influences on Ligand Binding and Receptor Functions

“…From the Genomic Data Commons database (version 22.0; as collected by Bongers et al) [ 22 , 23 ], a total of 58 A 2A AR single-site missense mutations were identified in patients of different cancer types. As shown in Figure 1 , these mutations were distributed all over the receptor.…”

“…Therefore, these 15 mutations were selected for further investigation. Of note, A265T ECL3 and S281L 7.46 have also been identified as natural variants (The 1000 Genomes Project Consortium, as collected by Bongers et al) [ 23 , 25 ], while the other mutations could be considered cancer specific ( Table S1 ).…”

Cancer-Related Somatic Mutations in Transmembrane Helices Alter Adenosine A1 Receptor Pharmacology

“…Previous structural studies and crystal structures of hA 1 AR provided us with information on crucial residues for ligand binding and receptor activation, as well as essential interactions in the inactive receptor state and G protein coupling [17,[23][24][25]. Moreover, compared to other residues, accumulation of cancer-related mutations has been observed in highly conserved residues of the TM domains [26]. Therefore, in this study, we studied 13 single-site point mutations located at the 7-TM domains of A 1 AR obtained from The Cancer Genome Atlas (TCGA).…”