title: Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies.
abstract: Synchronous colorectal carcinomas (sCRC) are clinically challenging neoplasms. Although the epidemiological characteristics are quite well established, their biological basis is still poorly understood. Hence, we performed comprehensive molecular profiling of 23 sCRC cases comprising 50 synchronous primary tumors, 5 metastases, and corresponding normal tissue by targeted deep sequencing of 30 CRC-related genes, microsatellite analysis and analysis for methylated MLH1. We identified a striking inter- and intratumoral genetic heterogeneity of sCRC. Twenty (87%) cases showed genetic heterogeneity leaving only three cases with tumors that had an identical genetic make-up. Intertumoral heterogeneity was frequently observed for clinically actionable genes, including KRAS. Specifically, 44% of the cases harbored tumors of which at least one was KRAS mutated and the other KRAS wildtype. Moreover, 48% of the cases had at least double, sometimes even triple or quadruple mutations in KRAS, APC, TP53, PIK3CA, and TGFBR2, most of them being subclonal events. Lastly, we detected four cases (17%) with microsatellite instable (MSI) tumors with one case harboring one MSI- and a distinct microsatellite stable carcinoma. Our data demonstrate a striking genetic heterogeneity not only between different sCRC of a single case but also within a single tumor. These results contribute to the biological understanding of sCRC and directly impact genotyping strategies and oncological decision making. Testing one tumor or a single metastasis may not suffice in the sCRC setting as clinically relevant and tumor-specific genetic information may be left undetected compromising optimal oncological therapy. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.|Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Jesinghaus
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.|Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.affiliation: Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Tavernar
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Muckenhuber
authors.affiliation: Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.|Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, Heidelberg, Germany.|Member of the German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|National Center for Tumor Diseases, Heidelberg, Germany.|National Center for Tumor Diseases, Heidelberg School of Oncology (NCT-HSO), Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D019175:DNA Methylation; D005260:Female; D018740:Genetic Heterogeneity; D060005:Genotyping Techniques / Q000379:methods; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D016283:Proto-Oncogene Proteins p21(ras)