Spatial niche formation but not malignant progression is a driving force for intratumoural heterogeneity.
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.
Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
Rouven
R
Hoefflin
Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Im Neuenheimer Feld 267, D-60120 Heidelberg, Germany.
Bernd
B
Lahrmann
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Gregor
G
Warsow
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.|Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, University of Heidelberg, Im Neuenheimer Feld 267, D-69120 Heidelberg, Germany.|Department of Pediatric Immunology, Hematology and Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany.
Daniel
D
Hübschmann
National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Cathleen
C
Spath
Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
Britta
B
Walter
Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
Xin
X
Chen
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Luisa
L
Hofer
Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
Stephan
S
Macher-Goeppinger
Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
Yanis
Y
Tolstov
Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, Medical Faculty Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.
Nina
N
Korzeniewski
University of Pittsburgh Cancer Institute, Cancer Therapeutics Program, 5117 Centre Avenue, Pittsburgh, Pennsylvania 15232, USA.
Anette
A
Duensing
National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Carsten
C
Grüllich
National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Dirk
D
Jäger
Institute of Pathology, University Hospital Lübeck and Leibniz Research Center Borstel, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
Sven
S
Perner
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Gita
G
Schönberg
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Joanne
J
Nyarangi-Dix
National Center for Tumor Diseases, Department of Medical Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Sanjay
S
Isaac
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Gencay
G
Hatiboglu
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Dogu
D
Teber
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Boris
B
Hadaschik
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Sascha
S
Pahernik
Department of Pathology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 224, D-69120 Heidelberg, Germany.
Wilfried
W
Roth
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.|Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, University of Heidelberg, Im Neuenheimer Feld 267, D-69120 Heidelberg, Germany.
Roland
R
Eils
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Matthias
M
Schlesner
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.
Holger
H
Sültmann
Department of Urology, University of Heidelberg School of Medicine, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Markus
M
Hohenfellner
Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Im Neuenheimer Feld 267, D-60120 Heidelberg, Germany.
Niels
N
Grabe
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.|Center for Kidney Tumors, National Center for Tumor Diseases and University of Heidelberg School of Medicine, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.
Stefan
S
Duensing
D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D018740:Genetic Heterogeneity; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D015398:Signal Transduction; D059016:Tumor Microenvironment; D000073359:Exome Sequencing
D014408:Biomarkers, Tumor