Pathway and network analysis of more than 2500 whole cancer genomes.

Reyna, Matthew A; Haan, David; Paczkowska, Marta; Verbeke, Lieven P C; Vazquez, Miguel; Kahraman, Abdullah; Pulido-Tamayo, Sergio; Barenboim, Jonathan; Wadi, Lina; Dhingra, Priyanka; Shrestha, Raunak; Getz, Gad; Lawrence, Michael S; Pedersen, Jakob Skou; Rubin, Mark Andrew; Wheeler, David A; Brunak, Søren; Izarzugaza, Jose M G; Khurana, Ekta; Marchal, Kathleen; ... (2020). Pathway and network analysis of more than 2500 whole cancer genomes. Nature communications, 11(1), p. 729. Nature Publishing Group 10.1038/s41467-020-14367-0

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The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Rubin, Mark Andrew and Johnson, Rory Baldwin

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Rebeka Gerber

Date Deposited:

28 Aug 2020 15:21

Last Modified:

13 Mar 2021 23:08

Publisher DOI:

10.1038/s41467-020-14367-0

PubMed ID:

32024854

Additional Information:

Collaborator PCAWG Drivers and Functional Interpretation Working Group: Johnson, Rory

BORIS DOI:

10.7892/boris.146112

URI:

https://boris.unibe.ch/id/eprint/146112

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