Journal Article

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

Huebschmann, Daniel, Toprak, Umut H., Hutter, Barbara, Gu, Zuguang, Ishaque, Naveed, Benner, Axel, Kozlowski, Miroslaw, Shavinskaya, Anna, Reszec, Joanna, Eils, Roland, Schlesner, Matthias, Niklinski, Jacek, Paramasivam, Nagarajan, Zhou, Chan, Patil, Nitin, Kerssemakers, Jules, Abba, Mohammed L., Hauser, Christine, Moniuszko, Marcin, Marx, Alexander, Kleinheinz, Kortine, Eils, Jürgen, Leupold, Jörg Hendrik, Allgayer, Heike, Balasubramanian, Gnana Prakash, Brors, Benedikt

2018

Overview

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. The evolution and genetic nature of metastatic lesions is not completely characterized. Here the authors perform a comprehensive whole-genome study of colorectal metastases in comparison to matched primary tumors and define a multistage progression model and metastasis-specific changes that, in part, are therapeutically actionable.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 3' Untranslated Regions - genetics / 38/43 / 45/23 / 631/114/2785/2302 / 631/67/69 / Adaptor Proteins, Signal Transducing - genetics / Adenocarcinoma - genetics / Adenocarcinoma - secondary / Aged / AKT protein / AKT2 protein / Anoctamins - genetics / BRCA2 protein / BRCA2 Protein - genetics / Breast cancer / Cell adhesion / Cell adhesion & migration / Cell Adhesion - genetics / Colonization / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Colorectal Neoplasms - therapy / Evolution / Extracellular matrix / Extracellular Matrix - genetics / Female / Fibroblast growth factor 1 / Forkhead Transcription Factors - genetics / Foxp2 protein / Gene sequencing / Genetic programs / Genomes / Hepatic Stellate Cells - metabolism / Humanities and Social Sciences / Humans / Hypotheses / Immunosuppression / Lesions / Liver Neoplasms - genetics / Liver Neoplasms - secondary / Male / Membrane Transport Proteins - genetics / Metastases / Metastasis / Middle Aged / multidisciplinary / Mutation / Neoplasm Metastasis / Nuclear Proteins - genetics / PD-L1 protein / Precision Medicine / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-cbl - genetics / Receptor, Platelet-Derived Growth Factor alpha - genetics / Rho Guanine Nucleotide Exchange Factors - genetics / RNA, Untranslated / Science / Science (multidisciplinary) / Signal Transduction / Therapy / Transcription activation / Transcription Factors - genetics / Transient receptor potential proteins / TRPM Cation Channels - genetics / Tumors / Vascular Endothelial Growth Factor Receptor-2 - genetics / Whole Genome Sequencing