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Signatures of mutational processes in human cancer

Ludmil B Alexandrov1, Serena Nik-Zainal, David C Wedge

  • 1Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

Nature
|August 16, 2013
PubMed

Insights

Cancer development is driven by somatic mutations. This study identified over 20 distinct mutational signatures across 7,042 cancers, revealing diverse biological processes and potential therapeutic targets.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Somatic mutations are the fundamental cause of all cancers.
  • Understanding the biological processes that generate these mutations is crucial but limited.
  • Cancer genomes contain signatures reflecting the mutational processes involved.

Purpose of the Study:

  • To analyze a large dataset of cancer mutations to identify and characterize mutational signatures.
  • To explore the origins and associations of these signatures with clinical and etiological factors.
  • To investigate localized hypermutation events ('kataegis') in cancer genomes.

Main Methods:

  • Analysis of 4,938,362 mutations from 7,042 cancer samples.
  • Extraction and classification of distinct mutational signatures.
  • Correlation of signatures with patient age, mutagenic exposures, and DNA repair defects.

Main Results:

  • Identification of over 20 distinct mutational signatures.
  • Discovery of signatures associated with APOBEC enzymes, patient age, and DNA maintenance.
  • Observation of cryptic signatures and localized hypermutation (kataegis) in various cancer types.
  • Demonstration of diverse mutational processes underlying cancer development.

Conclusions:

  • The study reveals a wide spectrum of mutational processes contributing to cancer.
  • Mutational signatures offer insights into cancer etiology, prevention, and treatment strategies.
  • Further research into cryptic signatures and kataegis could uncover novel therapeutic avenues.

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