3.2 Widespread mutations in GPCRs

Studies have identified widespread mutations of GPCRs in cancer (Sriramet al. , 2019). By analyzing 5,103 samples of 20 tumor types from The Cancer Genome Atlas (TCGA), Sriram et al. found that approximately 65% of tumors have at least 1 nonsilent GPCR mutation. This frequency is higher than the previously reported 20% by Kanet al. (Kan et al., 2010), which may lie in different sampling methods. Kan’s study included 441 tumor samples (183 breast cancers, 134 of lung cancers, 58 ovarian, 58 prostate and 8 pancreatic cancers), for which only 156 GPCRs were analyzed. While more samples were inlcuded in Sriram’s study, and almost all GPCRs annotated by GtoPdb were analyzed, including taste and vision receptors but not olfactory GPCRs. On one hand, this comprehensive analysis suggests a previously underappreciated role for GPCRs in cancer. On the other hand, given the large number of GPCR family members, even if certain receptors have very low mutation frequency in cancer, the overall mutation rate of GPCRs may be overestimated. Apart from the overall mutational burden, they also found GPR98/ADGRV1 the most frequently mutated GPCR, occurring in more than 8% of TCGA samples, and that approximately 40% SKCM tumors have a GPR98 mutation. Similarly, reoccurring high-impact GPCR mutations, predominantly found in class A GPCRs, are observed in UCEC, SKCM, LUAD, COAD, and STAD (Huh et al. , 2021).
These GPCR mutations in cancer can lead to various biological consequences. For example, mutated receptors like the thyroid-stimulating hormone receptor (TSHR) and lutropin receptor (LHR) share a common ability to increase cAMP (Bonomi et al. , 2001; G. Liu et al. , 1999; Miyai, 2007). The activation of MAPK/ERK and mTor pathway was affected by mutants of the melanocortin 1 receptor (MC1R) (JA & Bishop, 2005; Turan et al. , 2012). Mutants of the melanocortin 2 receptor (MC2R) exhibit a unique defect in trafficking to the cell surface (Flück, Martens, Conte, & Miller, 2002). And the mutated smoothened receptor (SMO) was found to change the constitutive activity of the Hedgehog pathway (Reifenberger et al. , 1998; Wanget al. , 2014). The frequently observed mutated GPCRs in cancer are shown in Table 3, which highlights the variety of GPCR signaling pathways involved in cancer.
Table 3 Frequently observed mutated GPCRs in cancer. This list is adapted from the review: “An Insight into GPCR and G-Proteins as Cancer Drivers” by Kim et al. (Chaudhary & Kim, 2021).