Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors

Abstract

G Protein-coupled receptors (GPCRs) are the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used a dataset of mutations found in 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. We explored cancer-related mutation patterns in all GPCR classes combined and individually. While the location of the mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment in cancer patients was observed among class-specific conserved motifs in GPCRs such as the Class A “DRY” motif. A Two-Entropy Analysis confirmed the correlation between residue conservation and cancer-related mutation frequency. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). Our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, but also discovered novel GPCRs which had not been linked to cancer before such as the P2Y Receptor 10 (P2RY10). Overall, this study presents a list of GPCRs that are amenable to experimental follow up to elucidate their role in cancer.

3DDPDs: describing protein dynamics for proteochemometric bioactivity prediction. A case for (mutant) G protein-coupled receptors

“…An alternative would be to compute ps3DDPDs for particular regions of interest. For instance, we suggest analyzing functionally relevant residues derived from rs3DDPD feature importance, from observations in the RMSF analysis, or the literature (for example for cancer-related mutants [24]).…”

“…In the last decades, the scientific community has seen an increasing interest in the dynamic aspects of GPCRs, resulting in community efforts such as the GPCRmd database, where curated GPCR MD simulations are publicly available [23]. Simultaneously, GPCR research in the context of oncological therapies is gaining momentum [24], with several in vitro studies showing how cancer-related somatic mutations affect receptor function and/or pharmacological intervention [25][26][27]. Some of the physiological effects observed in mutants have been associated with changes in receptor dynamics thanks to MD simulations [28].…”

The lncRNA TRG-AS1 promotes the growth of colorectal cancer cells through the regulation of P2RY10/GNA13

“…In addition, by acting as a competing endogenous RNA (ceRNA) for miR-877-5p, TRG-AS1 mediated SUZ12 expression and promoted glioblastoma cell proliferation, thus representing a novel therapeutic target for glioblastoma. In CRC, P2RY10 is co-expressed with lncRNA TRG-AS1 and is associated with chemotaxis through eosinophil degranulation, which may be a potential target for cancer treatment [26]. P2RY10 expression is increased in synovial tissues and peripheral blood in patients with rheumatoid arthritis and coronary artery disease [27], and the LysoPS-P2Y10 axis has been shown to inhibit TNF-α production in mouse microglia and activate eosinophilic degranulation [17].…”

Molecular insights into disease-associated glutamate transporter (EAAT1 / SLC1A3) variants using in silico and in vitro approaches

“…Cancer-related mutations were obtained from the Genomic Data Commons (M. A. Jensen et al, 2017) version 22.0 released on 16 January 2020, as re-compiled by Bongers et al (2022). Somatic missense mutations were retrieved for gene SLC1A3 (EAAT1) in all cancer types.…”