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Åke Borg

Åke Borg

Principal investigator

Åke Borg

Pathway and network analysis of more than 2500 whole cancer genomes

Author

  • Matthew A Reyna
  • David Haan
  • Marta Paczkowska
  • Lieven P C Verbeke
  • Miguel Vazquez
  • Abdullah Kahraman
  • Sergio Pulido-Tamayo
  • Jonathan Barenboim
  • Lina Wadi
  • Priyanka Dhingra
  • Raunak Shrestha
  • Gad Getz
  • Michael S Lawrence
  • Jakob Skou Pedersen
  • Mark A Rubin
  • David A Wheeler
  • Søren Brunak
  • Jose M G Izarzugaza
  • Ekta Khurana
  • Kathleen Marchal
  • Christian von Mering
  • S Cenk Sahinalp
  • Alfonso Valencia
  • Joshua M Stuart
  • Jüri Reimand
  • Benjamin J Raphael
  • Federico Abascal
  • Lihua Zou
Show all

Other contributions

  • Åke Borg
  • Markus Ringnér
  • Johan Staaf

Summary, in English

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.

Department/s

  • LUCC: Lund University Cancer Centre
  • Familial Breast Cancer
  • Breastcancer-genetics
  • Molecular Cell Biology
  • Breast/lungcancer
  • Research Group Lung Cancer

Publishing year

2020-02-05

Language

English

Publication/Series

Nature Communications

Volume

11

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Medical Genetics

Keywords

  • Chromatin Assembly and Disassembly
  • Computational Biology/methods
  • Databases, Genetic
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Humans
  • Metabolic Networks and Pathways/genetics
  • Mutation
  • Neoplasms/genetics
  • Promoter Regions, Genetic
  • RNA Splicing

Status

Published

Research group

  • Familial Breast Cancer
  • Research Group Lung Cancer

ISBN/ISSN/Other

  • ISSN: 2041-1723