Abstract

Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3’ UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3’ UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy.

Details

Title
Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer
Author
Ishaque, Naveed 1 ; Abba, Mohammed L 2 ; Hauser, Christine 2 ; Patil, Nitin 2 ; Nagarajan Paramasivam 3 ; Huebschmann, Daniel 4   VIAFID ORCID Logo  ; Leupold, Jörg Hendrik 2 ; Balasubramanian, Gnana Prakash 5 ; Kleinheinz, Kortine 4   VIAFID ORCID Logo  ; Toprak, Umut H 4 ; Hutter, Barbara 5   VIAFID ORCID Logo  ; Benner, Axel 6 ; Shavinskaya, Anna 7 ; Chan, Zhou 2 ; Gu, Zuguang 8 ; Kerssemakers, Jules 4   VIAFID ORCID Logo  ; Marx, Alexander 9 ; Moniuszko, Marcin 10 ; Kozlowski, Miroslaw 10 ; Reszec, Joanna 10 ; Niklinski, Jacek 10 ; Eils, Jürgen 4 ; Schlesner, Matthias 11   VIAFID ORCID Logo  ; Eils, Roland 12   VIAFID ORCID Logo  ; Brors, Benedikt 13   VIAFID ORCID Logo  ; Allgayer, Heike 2   VIAFID ORCID Logo 

1  Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580, Heidelberg, Germany; Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 
2  Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, 69120 Mannheim, Germany; Centre for Biomedicine and Medical Technology Mannheim (CBTM), 68167 Mannheim, Germany 
3  Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Ruprecht Karls University Heidelberg, Heidelberg, Germany 
4  Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 
5  Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany 
6  Department of Biostatistics, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany 
7  Department of Experimental Surgery-Cancer Metastasis, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, 69120 Mannheim, Germany 
8  Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580, Heidelberg, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 
9  Institute of Pathology, University Hospital Mannheim (UMM), 68167 Mannheim, Germany 
10  Faculty of Medicine, Medical University of Bialystok, 15-269 Bialystok, Poland 
11  Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 
12  Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580, Heidelberg, Germany; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Ruprecht Karls University Heidelberg, 69120 Heidelberg, Germany 
13  Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany 
Pages
1-14
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07041-z
ProQuest document ID
2133418914
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.