Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour
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...
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doaj-1a21f129c3f148418585e94b387517752020-11-25T02:14:49ZengMDPI AGCancers2072-66942019-06-0111681210.3390/cancers11060812cancers11060812Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary TumourParanita Ferronika0Joost Hof1Gursah Kats-Ugurlu2Rolf H. Sijmons3Martijn M. Terpstra4Kim de Lange5Annemarie Leliveld-Kors6Helga Westers7Klaas Kok8Department of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, HPC EA10, 9700 RB Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsDepartment of Urology, University of Groningen, University Medical Center Groningen, HPC CB60, 9700 RB Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, HPC CB50, 9700 RB Groningen, The NetherlandsWhile 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.https://www.mdpi.com/2072-6694/11/6/812intratumour heterogeneitymetastatic ccRCCcopy number alterationmutationgene expression |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paranita Ferronika Joost Hof Gursah Kats-Ugurlu Rolf H. Sijmons Martijn M. Terpstra Kim de Lange Annemarie Leliveld-Kors Helga Westers Klaas Kok |
spellingShingle |
Paranita Ferronika Joost Hof Gursah Kats-Ugurlu Rolf H. Sijmons Martijn M. Terpstra Kim de Lange Annemarie Leliveld-Kors Helga Westers Klaas Kok Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour Cancers intratumour heterogeneity metastatic ccRCC copy number alteration mutation gene expression |
author_facet |
Paranita Ferronika Joost Hof Gursah Kats-Ugurlu Rolf H. Sijmons Martijn M. Terpstra Kim de Lange Annemarie Leliveld-Kors Helga Westers Klaas Kok |
author_sort |
Paranita Ferronika |
title |
Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour |
title_short |
Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour |
title_full |
Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour |
title_fullStr |
Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour |
title_full_unstemmed |
Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour |
title_sort |
comprehensive profiling of primary and metastatic ccrcc reveals a high homology of the metastases to a subregion of the primary tumour |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-06-01 |
description |
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. |
topic |
intratumour heterogeneity metastatic ccRCC copy number alteration mutation gene expression |
url |
https://www.mdpi.com/2072-6694/11/6/812 |
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