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.