title: Distinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal Cancer.
abstract: A multistep model of disease progression and genomic landscape has been firmly established for colorectal cancer (CRC) primaries, but the genetic makeup of related metastases and the dynamics of genetic changes during metastatic progression are scarcely known. To address these issues, we used multigene high-coverage next-generation sequencing of 24 microsatellite-stable CRC primaries, matched normal tissue, and related multiple metastases to nodes, liver, lung, and brain with a CRC-specific gene panel to infer the degree of clonal evolution during metastatic progression of the disease. Somatic mutations were detected in 40% of CRC-related genes, and we observed a striking 100% genetic concordance between primary and multiple secondary sites for APC, KRAS, FBXW7, PIK3CA, BRAF, SMAD4, and ACVR2A. Except for true de novo mutations in 4 cases (affecting SYNE1, CTNNB1, TP53, and PTEN), all remaining cases (84.4%) shared the genetic lesions of the primary tumors with all investigated metastases irrespective of the site of metastasis or time lapse between primary tumor resection and the occurrence of metastatic spread. Putative biomarkers and druggable targets were identified in 25% of the cases. Our data proves that genetic alterations occurring early in CRC carcinogenesis are remarkably stable during metastatic progression, indicating (i) a very low degree of genetic heterogeneity between primary and multiple secondary sites with respect to CRC driver mutations and (ii) that genetic interrogation of archived primary tumor samples appears to be sufficient for the application of cancer precision medicine in the metastatic setting.
authors.affiliation: Departments of *General Pathology †Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg ‡Clinical Cooperation Unit Applied Tumor Biology, DKFZ ∥National Center for Tumor Diseases (NCT), Heidelberg §Institute of Pathology, Charité University Medicine, Berlin, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Jesinghaus
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.forename: Alexander
authors.initials: A
authors.lastname: Muckenhuber
authors.forename: Aysel
authors.initials: A
authors.lastname: Ahadova
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.forename: Benjamin
authors.initials: B
authors.lastname: Goeppert
authors.forename: Christine
authors.initials: C
authors.lastname: Sers
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor