Intratumoural heterogeneity (ITH) is a major cause of cancer-associated lethality. Extensive genomic ITH has previously been reported in clear cell renal cell carcinoma (ccRCC). Here we address the question whether ITH increases with malignant progression and can hence be exploited as a prognostic marker. Unexpectedly, precision quantitative image analysis reveals that the degree of functional ITH is virtually identical between primary ccRCCs of the lowest stage and advanced, metastatic tumours. Functional ITH was found to show a stage-independent topological pattern with peak proliferative and signalling activities almost exclusively in the tumour periphery. Exome sequencing of matching peripheral and central primary tumour specimens reveals various region-specific mutations. However, these mutations cannot directly explain the zonal pattern suggesting a role of microenvironmental factors in shaping functional ITH. In conclusion, our results indicate that ITH is an early and general characteristic of malignant growth rather than a consequence of malignant progression.
Nature communications. 2016 Jun 13*** epublish ***
Rouven Hoefflin, Bernd Lahrmann, Gregor Warsow, Daniel Hübschmann, Cathleen Spath, Britta Walter, Xin Chen, Luisa Hofer, Stephan Macher-Goeppinger, Yanis Tolstov, Nina Korzeniewski, Anette Duensing, Carsten Grüllich, Dirk Jäger, Sven Perner, Gita Schönberg, Joanne Nyarangi-Dix, Sanjay Isaac, Gencay Hatiboglu, Dogu Teber, Boris Hadaschik, Sascha Pahernik, Wilfried Roth, Roland Eils, Matthias Schlesner, Holger Sültmann, Markus Hohenfellner, Niels Grabe, Stefan Duensing
Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Im Neuenheimer Feld 267, D-60120 Heidelberg, Germany., Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany., Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany., National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany., Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany., Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany., University of Pittsburgh Cancer Institute, Cancer Therapeutics Program, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15232, USA., National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Institute of Pathology, University Hospital Lübeck and Leibniz Research Center Borstel, Ratzeburger Allee 160, D-23538 Lübeck, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany., Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany., Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany., National Center for Tumor Diseases, German Cancer Research Center, Division of Cancer Genome Research, German Cancer Consortium (DKTK), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany., Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany., Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Im Neuenheimer Feld 267, D-60120 Heidelberg, Germany., Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.