Genomic alterations impact cell cycle-related genes during prostate cancer progression

Abstract

The recent genomic characterization of patient specimens has started to reveal the landscape of somatic alterations in clinical prostate cancer (CaP) and its association with disease progression and treatment resistance. The extent to which such alterations impact hallmarks of cancer is still unclear. Here, we interrogate genomic data from thousands of clinical CaP specimens that reflect progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP for alterations in cell cycle-associated and -regulated genes, which are central to cancer initiation and progression. We evaluate gene signatures previously curated to evaluate G1-S and G2-M phase transitions or to represent the cell cycle-dependent proteome. The resulting CaP (stage)-specific overview confirmed the presence of well-known driver alterations impacting, for instance, the genes encoding p53 and MYC, and uncovered novel previously unrecognized mutations that affect others such as the PKMYT1 and MTBP genes. The cancer dependency and drugability of representative genomically altered cell cycle determinants were verified also. Taken together, these analyses on hundreds of often less-characterized cell cycle regulators expand considerably the scope of genomic alterations associated with CaP cell proliferation and cell cycle and isolate such regulatory proteins as putative drivers of CaP treatment resistance and entirely novel therapeutic targets for CaP therapy.

Keywords: cell proliferation; driver mutation; precision medicine; treatment resistance.

Figure 1.. Quantitative view of genomic alteration rate among the membership of the 3 cell cycle-related gene signatures in cBio CaP datasets.

The X-axis represents the membership of 6 individual LOC, 4 individual CRCP and 2 individual NEPC cBIO datasets. Dots reflect alteration rate per gene for each gene signature and dataset. Y-axis lists the alteration rate as proportion of cases with alterations, in which 0 means that no cases show an alteration and 1 that all cases in that study do. The source data for Figure 1 were retrieved from the cBIO portal in November 2020 and are available upon request. In brief, members of each cell cycle-related gene signature (G1-S, G2-M, cell cycle-dependent proteome signature) were queried across each of the 12 cBIO studies using default cBio settings. Only data for mutations and copy number alterations were collected and shown. The percentage of alterations for each gene was retrieved using default cBIO settings. GO, Gene Ontology; LOC, localized treatment-naïve CaP; CRPC, castration-resistant CaP; NEPC, neuroendocrine CaP.

Figure 2.. Qualitative overview of the genomic alteration rate per CaP stage for each gene included in the 3 cell cycle-derived signatures in cBio CaP datasets.

Rate of alterations in all genes derived form G1-S phase transition (A), G2-M phase transition (B), and cell cycle-dependent proteome signature (C) are presented. Somatic alterations discussed in more detail in the text are labelled. Source data was retrieved from the cBio portal in November of 2020 as described in legend to Figure 1 and are available upon request. LOC, localized treatment-naïve CaP; CRPC, castration-resistant CaP; NEPC, neuroendocrine CaP.