Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer

Naveed Ishaque, Mohammed L. Abba, Christine Hauser, Nitin Patil, Nagarajan Paramasivam, Daniel Huebschmann, Jörg Hendrik Leupold, Gnana Prakash Balasubramanian, Kortine Kleinheinz, Umut H. Toprak, Barbara Hutter, Axel Benner, Anna Shavinskaya, Chan Zhou, Zuguang Gu, Jules Kerssemakers, Alexander Marx, Marcin Moniuszko, Miroslaw Kozlowski, Joanna Reszec, Jacek Niklinski, Jürgen Eils, Matthias Schlesner, Roland Eils, Benedikt Brors and Heike Allgayer ()
Additional contact information
Naveed Ishaque: DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580
Mohammed L. Abba: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg
Christine Hauser: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg
Nitin Patil: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg
Nagarajan Paramasivam: German Cancer Research Center (DKFZ)
Daniel Huebschmann: German Cancer Research Center (DKFZ)
Jörg Hendrik Leupold: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg
Gnana Prakash Balasubramanian: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Kortine Kleinheinz: German Cancer Research Center (DKFZ)
Umut H. Toprak: German Cancer Research Center (DKFZ)
Barbara Hutter: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Axel Benner: German Cancer Research Centre (DKFZ)
Anna Shavinskaya: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg
Chan Zhou: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg
Zuguang Gu: DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580
Jules Kerssemakers: German Cancer Research Center (DKFZ)
Alexander Marx: University Hospital Mannheim (UMM)
Marcin Moniuszko: Medical University of Bialystok
Miroslaw Kozlowski: Medical University of Bialystok
Joanna Reszec: Medical University of Bialystok
Jacek Niklinski: Medical University of Bialystok
Jürgen Eils: German Cancer Research Center (DKFZ)
Matthias Schlesner: German Cancer Research Center (DKFZ)
Roland Eils: DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580
Benedikt Brors: German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Heike Allgayer: Medical Faculty Mannheim, Ruprecht Karls University Heidelberg

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07041-z

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