DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Soulafa Mamlouk - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)
  • Liam Harold Childs - , Humboldt University of Berlin (Author)
  • Daniela Aust - , Institute of Pathology, University Hospital Carl Gustav Carus Dresden, German Cancer Consortium (DKTK) Core Center Heidelberg (Author)
  • Daniel Heim - , Charité – Universitätsmedizin Berlin (Author)
  • Friederike Melching - , Charité – Universitätsmedizin Berlin (Author)
  • Cristiano Oliveira - , Heidelberg University  (Author)
  • Thomas Wolf - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Pawel Durek - , German Rheumatism Research Centre Berlin (Author)
  • Dirk Schumacher - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)
  • Hendrik Bläker - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)
  • Moritz Von Winterfeld - , Charité – Universitätsmedizin Berlin, University of Cologne (Author)
  • Bastian Gastl - , Charité – Universitätsmedizin Berlin (Author)
  • Kerstin Möhr - , Charité – Universitätsmedizin Berlin (Author)
  • Andrea Menne - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)
  • Silke Zeugner - , University Hospital Carl Gustav Carus Dresden, Institute of Pathology (Author)
  • Torben Redmer - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)
  • Dido Lenze - , Charité – Universitätsmedizin Berlin (Author)
  • Sascha Tierling - , Saarland University (Author)
  • Markus Möbs - , Charité – Universitätsmedizin Berlin (Author)
  • Wilko Weichert - , German Cancer Research Center (DKFZ), Technical University of Munich (Author)
  • Gunnar Folprecht - , Department of Internal Medicine I, University Cancer Centre Dresden, University Hospital Carl Gustav Carus Dresden (Author)
  • Eric Blanc - , Berlin Institute of Health at Charité, Charité – Universitätsmedizin Berlin (Author)
  • Dieter Beule - , Berlin Institute of Health at Charité, Max Delbrück Center for Molecular Medicine (MDC) (Author)
  • Reinhold Schäfer - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)
  • Markus Morkel - , Charité – Universitätsmedizin Berlin (Author)
  • Frederick Klauschen - , Charité – Universitätsmedizin Berlin (Author)
  • Ulf Leser - , Humboldt University of Berlin (Author)
  • Christine Sers - , Charité – Universitätsmedizin Berlin, German Cancer Research Center (DKFZ) (Author)

Abstract

Genetic heterogeneity between and within tumours is a major factor determining cancer progression and therapy response. Here we examined DNA sequence and DNA copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth sequencing of 100 most frequently altered genes. In 97 samples, with primary tumours and matched metastases from 27 patients, we observe inter-tumour concordance for coding mutations; in contrast, gene copy numbers are highly discordant between primary tumours and metastases as validated by fluorescent in situ hybridization. To further investigate intra-tumour heterogeneity, we dissected a single tumour into 68 spatially defined samples and sequenced them separately. We identify evenly distributed coding mutations in APC and TP53 in all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D morpho-molecular reconstruction reveals two clusters with divergent copy number aberrations along the proximal-distal axis indicating that DNA copy number variations are a major source of tumour heterogeneity in CRC.

Details

Original languageEnglish
Article number14093
JournalNature communications
Volume8
Publication statusPublished - 25 Jan 2017
Peer-reviewedYes

External IDs

PubMed 28120820
ORCID /0000-0002-9321-9911/work/164199010