Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

Abstract

Familial tumor suppressor genes comprise two subgroups: caretaker genes (CTs) that repair DNA, and gatekeeper genes (GKs) that trigger cell death. Since GKs may also induce cell cycle delay and thus enhance cell survival by facilitating DNA repair, we hypothesized that the prosurvival phenotype of GKs could be selected during cancer progression, and we used a multivariable systems biology approach to test this. We performed multidimensional data analysis, non-negative matrix factorization and logistic regression to compare the features of GKs with those of their putative antagonists, the proto-oncogenes (POs), as well as with control groups of CTs and functionally unrelated congenital heart disease genes (HDs). GKs and POs closely resemble each other, but not CTs or HDs, in terms of gene structure (Po0.001), expression level and breadth (Po0.01), DNA methylation signature (Po0.001) and evolutionary rate (Po0.001). The similar selection pressures and epigenetic trajectories of GKs and POs so implied suggest a common functional attribute that is strongly negatively selected-that is, a shared phenotype that enhances cell survival. The counterintuitive finding of similar evolutionary pressures affecting GKs and POs raises an intriguing possibility: namely, that cancer microevolution is accelerated by an epistatic cascade in which upstream suppressor gene defects subvert the normal bifunctionality of wild-type GKs by constitutively shifting the phenotype away from apoptosis towards survival. If correct, this interpretation would explain the hitherto unexplained phenomenon of frequent wild-type GK (for example, p53) overexpression in tumors.

Cellular Hyperproliferation and Cancer as Evolutionary Variables

“…This rapid rate of change in the allele frequencies of a population is known as microevolution (Box 1) [9]. That microevolutionary principles can help explain the incidence, pathology and characteristics of many human diseases has not gone unnoticed by the medical community [10–12]. This is particularly evident in studies in which population genetics have been applied to uncover the causes of disease susceptibility in human populations [13–18].…”

The Unpluggable in Pursuit of the Undruggable: Tackling the Dark Matter of the Cancer Therapeutics Universe

“…In 1997 Kinzler and Vogelstein noted that most tumor suppressor genes fall into just two functional categories: “caretaker” genes that repair DNA and maintain genetic stability, or “gatekeeper” genes that regulate cell-cycle progression and apoptosis (2). This semantic dichotomy is too simple (3), of course, given that genetic instability is exacerbated by gatekeeper gene defects that permit survival of cells which would otherwise self-destruct, whereas apoptotic resistance is worsened by caretaker defects that impair sensing of potentially lethal insults by the afferent limb of the DNA damage response (4). Nonetheless, as argued below, the potential utility of this model (5, 6) – contrasting as it does with more complex but less user-friendly models of cancer biology (7) – has not yet been exploited in clinical practice or research.…”

The secret identities of TMPRSS2: Fertility factor, virus trafficker, inflammation moderator, prostate protector and tumor suppressor

“…These findings do not exclude the possibility that TMPRSS2 plays different roles in different contexts, e.g., in the normal prostate, in the development of hormone-dependent invasive cancer, and/or in progression to castrate-resistant metastatic disease. Since cancer evolution may be associated with a gene changing its function due to epistatic effects [141] -with such genes comparable to electronic components, the effect of which depends upon placement in a circuit [142] -it is possible that in the metastatic context TMPRSS2, either independently or via interaction with other TTSPs [109], could drive tumor dissemination by a path involving, say, proteolytic activation of pro-HGF in extracellular matrix [22,25]. One study supporting this hypothesis showed that a recombinant TMPRSS2 inhibitor reduced prostate cancer cell invasion and metastasis [143]; however, the same inhibitor had earlier been reported to inhibit invasion and metastasis of lung cancer cells [144] for which TMPRSS2 is not a co-factor.…”