| Summary: | Summary: We systematically investigated the landscape of tumor-suppressor gene (TSG) inactivation events in 33 cancer types by quantitatively measuring their global and local genomic features and their transcriptional and signaling footprints. Using The Cancer Genome Atlas data, we identified with high confidence 337 TSG × cancer events in 30 cancer types, of which 277 were unique events. The majority (91.0%) of these events had a significant downstream impact measured by reduced expression of the TSG itself (cis-effect), disturbance of the transcriptome (trans-effect), or combinatorial effects. Importantly, the transcriptomic changes associated with TSG inactivation events were stronger than the cancer lineage difference, and the same TSGs inactivated in different cancer types tended to cluster together. Several TSGs (e.g., RB1, TP53, and CDKN2A) involved in the regulation of the cell-cycle-formed clusters. Finally, we constructed subnetworks of the TSG × cancer inactivation events, including the local genes frequently disturbed upon the inactivation events. : Jia and Zhao present a pan-cancer analysis of tumor-suppressor gene (TSG) inactivation events. They examine the genetic mutations that lead to TSG inactivation and the functional impact of TSG inactivation events. The results suggest that TSG × cancer inactivation events tend to cluster by TSG function, rather than by cancer lineage. Keywords: tumor suppressor gene, two-hit model, The Cancer Genome Atlas, transcriptome impact, cell cycle pathway, RB1, CDKN2A
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