Prostate cancer (PC) remains one of the main prevailing causes of mortality in men globally, with an estimated detection of 220,800 new cases and at least 12% or above fatality rate being reported every year. A number of factors have been linked to the disease pathogenesis. The role of TP53 and typically its mutational status have historically been debated in PC. However, recently p53 levels have been shown to dictate the molecular classifications of PC.
Several mouse models have been developed to study PC, including the so called TRAMP mouse, which develop prostate malignancies owing to the over-expression of prostate-specific SV40 large T antigen transgene. Besides being useful for studying PC pathogenesis, a tumour from a TRAMP mouse has also been the source of the now widely used mouse prostate cancer (TRAMP-C) cell lines, which are transplantable in syngeneic C57BL/6 mice and hence can be used in drug efficacy studies. It was shown that, out of the three cell lines (TRAMP-C1, C2 and C3) developed from three different regions of the same tumour, TRAMP-C3 does not confer tumorigenic potential in vivo, a finding that remains unexplained to date. The only analysis of potential genetic causes of the tumorigenic potential of the cell lines that was performed was to analyse expression of large T antigen and p53 protein by qRT-PCR and immunohistochemistry, respectively. A high p53 expression would mean it is mutant since it would not be able to trigger its own degradation via Mdm2. Their analyses showed that neither was expressed; therefore the authors claimed that the tumour cells had silenced the large T antigen but remained wild type for p53 (hence low expression).
Intra-tumour heterogeneity plays an important role across malignancies and is most likely the cause of variations seen within a given tumour. We hypothesised that the underlying genomic variations may be the probable cause of differential tumorigenic potential seen in these cell lines. To validate this, we subjected the three TRAMP-C cell lines (TRAMP-C1, C2 and C3) to whole-exome sequencing.