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Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

1
Department of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The Netherlands
2
Department of Pathology, Faculty of Medicine, Universitas Gadjah Mada, Public Health, and Nursing, Sekip Utara, 55281 Yogyakarta, Indonesia
3
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, HPC EA10, 9700 RB Groningen, The Netherlands
4
Department of Urology, University of Groningen, University Medical Center Groningen, HPC CB60, 9700 RB Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(6), 812; https://doi.org/10.3390/cancers11060812
Received: 17 May 2019 / Revised: 4 June 2019 / Accepted: 5 June 2019 / Published: 12 June 2019
(This article belongs to the Special Issue Renal Cell Carcinoma)
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Abstract

While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles. View Full-Text
Keywords: intratumour heterogeneity; metastatic ccRCC; copy number alteration; mutation; gene expression intratumour heterogeneity; metastatic ccRCC; copy number alteration; mutation; gene expression
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Ferronika, P.; Hof, J.; Kats-Ugurlu, G.; Sijmons, R.H.; Terpstra, M.M.; de Lange, K.; Leliveld-Kors, A.; Westers, H.; Kok, K. Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour. Cancers 2019, 11, 812.

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