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

Nat Commun. 2018 Nov 14;9(1):4782. doi: 10.1038/s41467-018-07041-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adaptor Proteins, Signal Transducing / genetics
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / secondary
  • Aged
  • Anoctamins / genetics
  • Apoptosis Regulatory Proteins
  • BRCA2 Protein / genetics
  • Cell Adhesion / genetics
  • Colorectal Neoplasms / 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 / genetics*
  • Liver Neoplasms / secondary
  • Male
  • Membrane Proteins
  • Membrane Transport Proteins / genetics
  • Middle Aged
  • Neoplasm Metastasis
  • Nuclear Proteins / genetics
  • Precision Medicine*
  • 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

Substances

  • 3' Untranslated Regions
  • ANO5 protein, human
  • ARHGEF7 protein, human
  • Adaptor Proteins, Signal Transducing
  • Anoctamins
  • Apoptosis Regulatory Proteins
  • BRCA2 Protein
  • BRCA2 protein, human
  • DACH2 protein, human
  • DNA-Binding Proteins
  • FOXP2 protein, human
  • Forkhead Transcription Factors
  • Membrane Proteins
  • Membrane Transport Proteins
  • Nuclear Proteins
  • RNA, Untranslated
  • Rho Guanine Nucleotide Exchange Factors
  • TRPM Cation Channels
  • TRPM3 protein, human
  • Transcription Factors
  • XKR4 protein, human
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • KDR protein, human
  • Receptor, Platelet-Derived Growth Factor alpha
  • Vascular Endothelial Growth Factor Receptor-2
  • AKT2 protein, human
  • AKT3 protein, human
  • Proto-Oncogene Proteins c-akt
  • CBL protein, human