Mamlouk, Soulafa, Childs, Liam Harold, Aust, Daniela, Heim, Daniel, Melching, Friederike, Oliveira, Cristiano, Wolf, Thomas, Durek, Pawel, Schumacher, Dirk ORCID: 0000-0002-0031-0063, Blaeker, Hendrik, von Winterfeld, Moritz, Gastl, Bastian, Moehr, Kerstin, Menne, Andrea, Zeugner, Silke, Redmer, Torben ORCID: 0000-0002-0050-9478, Lenze, Dido, Tierling, Sascha, Moebs, Markus, Weichert, Wilko, Folprecht, Gunnar ORCID: 0000-0002-9321-9911, Blanc, Eric, Beule, Dieter ORCID: 0000-0002-3284-0632, Schaefer, Reinhold, Morkel, Markus ORCID: 0000-0002-2553-9999, Klauschen, Frederick, Leser, Ulf and Sers, Christine (2017). DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer. Nat. Commun., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mamlouk, SoulafaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Childs, Liam HaroldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aust, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heim, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melching, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oliveira, CristianoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durek, PawelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, DirkUNSPECIFIEDorcid.org/0000-0002-0031-0063UNSPECIFIED
Blaeker, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Winterfeld, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gastl, BastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moehr, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menne, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeugner, SilkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Redmer, TorbenUNSPECIFIEDorcid.org/0000-0002-0050-9478UNSPECIFIED
Lenze, DidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tierling, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moebs, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weichert, WilkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Folprecht, GunnarUNSPECIFIEDorcid.org/0000-0002-9321-9911UNSPECIFIED
Blanc, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beule, DieterUNSPECIFIEDorcid.org/0000-0002-3284-0632UNSPECIFIED
Schaefer, ReinholdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morkel, MarkusUNSPECIFIEDorcid.org/0000-0002-2553-9999UNSPECIFIED
Klauschen, FrederickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leser, UlfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sers, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-242242
DOI: 10.1038/ncomms14093
Journal or Publication Title: Nat. Commun.
Volume: 8
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHROMOSOMAL INSTABILITY; SOMATIC MUTATIONS; TUMOR HETEROGENEITY; DRUG-SENSITIVITY; MATCHED PRIMARY; GASTRIC-CANCER; COLON-CANCER; CELL-LINES; PROGRESSION; EVOLUTIONMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24224

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