Figure 2 Mutational variants of GPCRs in cancer cells, listed
as deleterious mutations, passenger, weak drivers, and driver mutations.
Variants of GPCRs are shown with different colors on cell membrane.
Impact of mutations are shown as dial with effect on cell proliferation.
4.1 Definitions of cancer driver and
passenger
mutations
Driver mutations are the primary architects of oncogenesis, which confer
a selective advantage to the affected cells and thereby steer cells
towards uncontrolled growth and proliferation (Vogelstein et al. ,
2013). This advantage results from the activation of critical signaling
pathways, such as those regulating cell cycle progression, apoptosis
evasion, and DNA repair mechanisms (Bailey et al. , 2018). In a
tumor, there are typically two to eight mutations in ”driver genes”,
while the remaining mutations are considered passengers that do not
provide any selective growth advantage (Bozic et al. , 2010).
Passenger mutations are genetic alterations that occur incidentally
during the chaotic genomic landscape of cancer development. Unlike
driver mutations, they are carried along as collateral consequences of
the genomic instability inherent in cancer cells (Kumar et al. ,
2020). While passenger mutations may not directly contribute to the
oncogenic process, their presence can serve as a molecular fingerprint,
aiding in the characterization and classification of tumors (Salvadores,
Mas-Ponte, & Supek, 2019).
4.2 Positive and negative selection
in tumor growth
As illustrated in Figure 2, positive selection refers to the process by
which genetic alterations (including driver mutations) conferring a
growth or survival advantage to cancer cells become predominant. On the
other hand, cells carrying deleterious mutations are rendered a survival
disadvantage and thus are eliminated from the tumor population over
time, the so-called negative selection (Bányai, Trexler, Kerekes, Csuka,
& Patthy, 2021). Negative selection contributes to the maintenance of
genomic stability within cancer cells. Together with positive selection,
this purifying process is crucial for the overall evolution of tumor,
allowing it to acquire and retain genetic alterations that promote its
growth while discarding those that impede it. For example, research has
demonstrated that several chemokine receptors (e.g. CCR2, CCR5, CX3CR1)
exhibit robust indications of purifying selection in cancer (Bányaiet al. , 2021). Cells with passenger mutations are mostly under
neutral selection, while in some cases passenger mutations can act as
weak drivers. For example, they are involved in relapses of acute
promyelocytic leukemia by impeding drug response (Lehmann-Che et
al. , 2018). On the other hand, there is evidence indicating that the
accumulation of passenger mutations could slow cancer progression
related to enhanced immunity (McFarland et al. , 2017). As such,
whether a mutation is a passenger or driver, and to which direction it
promotes the selection process is highly context-dependent. Of note,
mutations that are currently seen as passenger may still hold the
potential to play an important role in cancer development and treatment,
and thus should not be neglected.
4.3 Evidence of GPCR mutations as
cancer driver gene
Because of the complex signaling network of GPCRs, illustrating the
functional impact of genetic alterations may require investigation for
each specific receptor, and a one-size-fits-all approach may be
difficult. As discussed in section 3, Q209 and R183 mutation ofGNAQ lead to persistent activation of the MAPK pathway and drive
uncontrolled cell growth in uveal melanoma (Onken et al. , 2008).
In comparison, less strong evidence has been found for GPCRs. Currently,
studies have demonstrated that many GPCRs are involved in cancer
progression and immune response, and have identified mutations
positively or negatively affecting the downstream signaling pathways
(examples in Table 3), but a clear role of specific GPCR mutations in
cancer is missing. However, indications can be observed on a more
general scale. Research indicates that a majority of
Gi-coupled GPCRs exhibit mutations in the DRY motif,
leading to loss of function. Interestingly, these mutations are always
found to be mutually exclusive with GNAS-activating mutations (Raimondiet al. , 2019). This raises the intriguing possibility that
mutations in Gi-coupled GPCRs may mimic GNAS-activating
mutations in increasing intracellular cAMP levels and thereby promoting
cancer progression.
4.4 Evidence of GPCR mutations as
passenger gene
GPCRs often participate in intricate signaling networks where multiple
receptors can activate similar downstream pathways. In this case, the
so-called “redundancy” arises from the existence of alternative
receptors and ligands that can compensate for the loss or alteration of
a particular GPCR, which allows the cell to maintain essential functions
without compromising its signaling integrity (Thompson, Canals, &
Poole, 2014). Therefore, if a GPCR mutation occurs in a region that is
functionally redundant with other receptors, the mutant GPCR may not
exert a unique or critical influence on the cellular signaling cascade.
Consequently, these mutations are less likely to confer a selective
growth advantage to cells and act as passenger mutations in cancer (Pon
& Marra, 2015). Apart from this, GPCRs are widely expressed in
different tissue and cell types (P. Insel et al. , 2012). However,
because of the widespread distribution of GPCR mutations across various
cancer types, each tumor showcases a distinct repertoire of mutated
GPCRs occurring at very low frequencies. Mutations that lack a distinct
impact on critical signaling pathways within a specific tissue are more
likely to be passenger mutations (Hao & Tatonetti, 2016). Therefore, we
can conclude that while certain GPCRs may act as drivers, most mutations
contribute to the broader genomic complexity without directly driving
oncogenic processes.