Pathway-based dissection of the genomic heterogeneity of cancer hallmarks’ acquisition with SLAPenrich

Abstract

Cancer hallmarks are evolutionary traits required by a tumour to develop. While extensively characterised, the way these traits are achieved through the accumulation of somatic mutations in key biological pathways is not fully understood. To shed light on this subject, we characterised the landscape of pathway alterations associated with somatic mutations observed in 4,415 patients across ten cancer types, using 374 orthogonal pathway gene-sets mapped onto canonical cancer hallmarks. Towards this end, we developed SLAPenrich: a computational method based on population-level statistics, freely available as an open source R package. Assembling the identified pathway alterations into sets of hallmark signatures allowed us to connect somatic mutations to clinically interpretable cancer mechanisms. Further, we explored the heterogeneity of these signatures, in terms of ratio of altered pathways associated with each individual hallmark, assuming that this is reflective of the extent of selective advantage provided to the cancer type under consideration. Our analysis revealed the predominance of certain hallmarks in specific cancer types, thus suggesting different evolutionary trajectories across cancer lineages. Finally, although many pathway alteration enrichments are guided by somatic mutations in frequently altered high-confidence cancer genes, excluding these driver mutations preserves the hallmark heterogeneity signatures, thus the detected hallmarks’ predominance across cancer types. As a consequence, we propose the hallmark signatures as a ground truth to characterise tails of infrequent genomic alterations and identify potential novel cancer driver genes and networks.

Widespread Post-transcriptional Attenuation of Genomic Copy-Number Variation in Cancer

“…Samples with a strong correlation with the signature would be predicted to have higher attenuation and could, for example, display a higher proteasomal capacity. Thus, we considered an independent cell line panel for which gene expression and drug response is available ( Iorio et al., 2016b ), and ranked the cell lines according to their predicted protein attenuation potential (see the STAR Methods ). Then we assessed the association between this predicted attenuation potential and drug-response measurements for 265 compounds (see the STAR Methods ) ( Figures 7 D and S4 D).…”

“…Gene expression measurements (E-MTAB-3610) acquired with Affymetrix Human Genome U219 array for approximately 1,000 cell lines was used in this analysis ( Iorio et al., 2016b ). Drug response measurements were obtained as the area under the curve (AUC) for 265 compounds ( Iorio et al., 2016b ).…”

“…Gene expression measurements (E-MTAB-3610) acquired with Affymetrix Human Genome U219 array for approximately 1,000 cell lines was used in this analysis ( Iorio et al., 2016b ). Drug response measurements were obtained as the area under the curve (AUC) for 265 compounds ( Iorio et al., 2016b ). Cell lines proteome attenuation potential was calculated by performing pearson correlation between their transcriptomics profile and the proteome attenuation potential signature derived from tumours.…”

Comparative molecular life history of spontaneous canine and human gliomas

“…epigenetic (Imielinski et al, 2012). A pool of known glioma and pan-cancer driver genes (Ceccarelli et al 2016;Gröbner et al, 2018;Bailey et al 2018) were mapped to hallmarks following a previously published computer-assisted manual curation method (Table S4) (Iorio et al, 2018). Total five cohorts were defined, i.e.…”

Patient Similarity Network of Newly Diagnosed Multiple Myeloma Identifies Patient Sub-groups with Distinct Genetic Features and Clinical Implications

“…4 provide a summary and a graphical representation of the results (Supp Table 23). The analysis was performed on a set of 456 pathways mapped onto 10 canonical cancer hallmarks 27 . Group 1(HD) was overall enriched for pathways in the tumor-promoting inflammation and immune evasion hallmarks.…”