Original ArticlesDistinctive Spatiotemporal Stability of Somatic Mutations in Metastasized Microsatellite-stable Colorectal CancerJesinghaus, Moritz MD*; Wolf, Thomas PhD*; Pfarr, Nicole MSc*; Muckenhuber, Alexander MD*; Ahadova, Aysel MSc†,‡; Warth, Arne MD, PhD*; Goeppert, Benjamin MD*; Sers, Christine PhD§; Kloor, Matthias MD, PhD†,‡; Endris, Volker PhD*; Stenzinger, Albrecht MD*; Weichert, Wilko MD, PhD*,∥Author Information 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 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website, www.ajsp.com. T.W., C.S., and W.W. are members of the German Cancer Consortium (DKTK). M.J. and T.W. contributed equally. A.S. and W.W. share last authorship. Author contributions: A.S. and W.W. conceived and designed the study and supervised experiments. M.J., A.S., W.W., A.W., and B.G. collected and analyzed CRC samples. N.P. and V.E. performed and supervised next-generation sequencing. M.K. and A.A. performed and supervised analysis of microsatellite stability. T.W., M.J., N.P., C.S., A.S., and W.W. analyzed next-generation sequencing data. A.S. and W.W. wrote the manuscript with contributions from C.S., M.J., T.W., A.W., M.K., N.P., and V.E. All authors read and approved the final manuscript. Conflicts of Interest and Source of Funding: Funded by the German Cancer Consortium (DKTK; to W.W. and C.S.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Albrecht Stenzinger, MD, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany (e-mail: email@example.com). The American Journal of Surgical Pathology: August 2015 - Volume 39 - Issue 8 - p 1140-1147 doi: 10.1097/PAS.0000000000000423 Buy SDC Metrics 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. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.