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).