title: DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer.
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.
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Soulafa
authors.initials: S
authors.lastname: Mamlouk
authors.affiliation: Knowledge Management in Bioinformatics, Humboldt University of Berlin, Berlin 10099, Germany.
authors.forename: Liam Harold
authors.initials: LH
authors.lastname: Childs
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany.|NCT Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Aust
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Heim
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Melching
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|Institute of Pathology, University of Heidelberg, Heidelberg 69120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, Berlin 10117, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Durek
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schumacher
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Bläker
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: von Winterfeld
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|BSIO Berlin School of Integrative Oncology, University Medicine Charité, Berlin 13353, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Gastl
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Möhr
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Menne
authors.affiliation: Institute for Pathology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Zeugner
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Redmer
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Dido
authors.initials: D
authors.lastname: Lenze
authors.affiliation: Department of Genetics/Epigenetics, FR8.3 Life Sciences, Saarland University, Saarbrücken 66123, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Tierling
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Möbs
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|Institute of Pathology, Technical University Munich, Munich 81675, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: University Hospital Carl Gustav Carus, University Cancer Center/Medical Dpt. I, Dresden 01307, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.affiliation: Core Unit Bioinformatics, Berlin Institute of Health, Berlin 10117, Germany.|Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.affiliation: Core Unit Bioinformatics, Berlin Institute of Health, Berlin 10117, Germany.|Max-Delbrück-Center for Molecular Medicine, Berlin 13125, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Beule
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schäfer
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Morkel
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.affiliation: Knowledge Management in Bioinformatics, Humboldt University of Berlin, Berlin 10099, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Leser
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.|German Cancer Consortium (DKTK), Heidelberg 69120, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073336:Whole Genome Sequencing
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53