1. Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.
- Author
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Ishaque N, Abba ML, Hauser C, Patil N, Paramasivam N, Huebschmann D, Leupold JH, Balasubramanian GP, Kleinheinz K, Toprak UH, Hutter B, Benner A, Shavinskaya A, Zhou C, Gu Z, Kerssemakers J, Marx A, Moniuszko M, Kozlowski M, Reszec J, Niklinski J, Eils J, Schlesner M, Eils R, Brors B, and Allgayer H
- Subjects
- 3' Untranslated Regions genetics, Adaptor Proteins, Signal Transducing genetics, Adenocarcinoma secondary, Aged, Anoctamins genetics, Apoptosis Regulatory Proteins, BRCA2 Protein genetics, Cell Adhesion genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, DNA-Binding Proteins, Extracellular Matrix genetics, Female, Forkhead Transcription Factors genetics, Hepatic Stellate Cells metabolism, Humans, Liver Neoplasms secondary, Male, Membrane Proteins, Membrane Transport Proteins genetics, Middle Aged, Neoplasm Metastasis, Nuclear Proteins genetics, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-cbl genetics, RNA, Untranslated, Receptor, Platelet-Derived Growth Factor alpha genetics, Rho Guanine Nucleotide Exchange Factors genetics, Signal Transduction, TRPM Cation Channels genetics, Transcription Factors genetics, Vascular Endothelial Growth Factor Receptor-2 genetics, Whole Genome Sequencing, Adenocarcinoma genetics, Colorectal Neoplasms genetics, Liver Neoplasms genetics, Precision Medicine
- 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.
- Published
- 2018
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