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

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Item Type:Article
Title:DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer
Creators Name:Mamlouk, S. and Childs, L.H. and Aust, D. and Heim, D. and Melching, F. and Oliveira, C. and Wolf, T. and Durek, P. and Schumacher, D. and Blaeker, H. and von Winterfeld, M. and Gastl, B. and Moehr, K. and Menne, A. and Zeugner, S. and Redmer, T. and Lenze, D. and Tierling, S. and Moebs, M. and Weichert, W. and Folprecht, G. and Blanc, E. and Beule, D. and Schaefer, R. and Morkel, M. and Klauschen, F. and Leser, U. and Sers, C.
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.
Keywords:Adenomatous Polyposis Coli Protein, Colorectal Neoplasms, DNA Copy Number Variations, DNA Mutational Analysis, Fluorescence In Situ Hybridization, Gene Dosage, High-Throughput Nucleotide Sequencing, Mutation, Tumor Suppressor Protein p53, Whole Genome Sequencing
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:14093
Date:25 January 2017
Official Publication:https://doi.org/10.1038/ncomms14093
PubMed:View item in PubMed

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