Pathway and network analysis of more than 2500 whole cancer genomes
0301 basic medicine
/dk/atira/pure/subjectarea/asjc/1600/1600; name=General Chemistry
Sustainable Development Goals
Medizin
General Physics and Astronomy
Medical Genetics and Genomics
PCAWG Drivers and Functional Interpretation Working Group
Ecology,Evolution & Ethology
Neoplasms
name=General Biochemistry,Genetics and Molecular Biology
Databases, Genetic
Medicine and Health Sciences
2.1 Biological and endogenous factors
3100 Physics and Astronomy
/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; name=SDG 3 - Good Health and Well-being
Precision Medicine
Càncer
Promoter Regions, Genetic
SDG 3
Cancer
Human Biology & Physiology
/dk/atira/pure/subjectarea/asjc/1300/1300
Genome
Q
Biological Sciences
1600 Chemistry
Medicinsk genetik och genomik
/dk/atira/pure/subjectarea/asjc/3100/3100; name=General Physics and Astronomy
3. Good health
TERT PROMOTER MUTATIONS
Gene Expression Regulation, Neoplastic
name=General Physics and Astronomy
/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Medical Genetics
Genetics & Genomics
/dk/atira/pure/subjectarea/asjc/1600/1600
Metabolic Networks and Pathways
Biotechnology
Human
EXPRESSION
570
GENES
1300 Biochemistry
572
PROTEINS
Science
RNA Splicing
Bioinformatics and Computational Biology
Radboudumc 17: Women's cancers RIHS: Radboud Institute for Health Sciences
610
Genetics and Molecular Biology
610 Medicine & health
Article
Promoter Regions
Databases
03 medical and health sciences
Rare Diseases
Cancer Genomics
Genetic
/dk/atira/pure/subjectarea/asjc/1300/1300; name=General Biochemistry,Genetics and Molecular Biology
Genetics
cancer
Humans
Medicinsk genetik
Computational & Systems Biology
Neoplastic
Genome, Human
Human Genome
protein-coding
Biology and Life Sciences
PCAWG Consortium
Computational Biology
TLE4
General Chemistry
SOMATIC MUTATIONS
Tumour Biology
mutations
Chromatin Assembly and Disassembly
ENCYCLOPEDIA
Radboudumc 17: Women's cancers RIMLS: Radboud Institute for Molecular Life Sciences
name=SDG 3 - Good Health and Well-being
Genòmica
Gene Expression Regulation
Pan-Cancer Analysis of Whole Genomes (PCAWG)
DISCOVERY
General Biochemistry
Mutation
/dk/atira/pure/subjectarea/asjc/3100/3100
name=General Chemistry
Genètica
protein-coding genes, Mutation, genome sequencing, RNA splicing, cancer genomes
Structural Biology & Biophysics
DOI:
10.1038/s41467-020-14367-0
Publication Date:
2020-02-05T19:03:29Z
AUTHORS (1455)
ABSTRACT
AbstractThe 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.
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