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

Paranita Ferronika,Annemarie Leliveld-Kors,Gursah Kats-Ugurlu,Kim De Lange,Klaas Kok,Joost Hof,Martijn M Terpstra,Rolf H Sijmons,Helga Westers

doi:10.3390/cancers11060812

Paranita Ferronika, Annemarie Leliveld-Kors + Show 7 more

Open Access

https://doi.org/10.3390/cancers11060812

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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.

Highlights

Kidney cancer is a usually lethal urologic malignancy with an annual mortality rate of 50% and an annual incidence of 337,000 new cases worldwide [1]
Array comparative genomic hybridization (CGH)-based copy number profiles were generated for three primary tumour samples (Pr1, Pr3, and Pr4), the inferior vena cava tumour thrombus (VT), and four lung metastases (M1–M4) of the index patient (Figure 1)
We observed intermediate copy number states at varying positions in all primary tumour samples, which was indicative of intra-sample heterogeneity in copy number levels

Summary

Introduction

Kidney cancer is a usually lethal urologic malignancy with an annual mortality rate of 50% and an annual incidence of 337,000 new cases worldwide [1]. Somatic mutation and RNA expression profiles of primary ccRCC have been extensively described in the Cancer Genome Atlas project [4], the genomic profiles of metastatic ccRCC have not been frequently studied in the context of their primary tumours. In the few reported cases, intra primary tumour and metastasis heterogeneity was identified based on differences in copy number aberrations (CNAs) [5], single nucleotide variants (SNVs) [5,6] and RNA expression patterns [5,7]. As the majority of metastases are thought to establish through hematogenous dissemination [8], studying venous tumour thrombus samples may reveal the mutations of at least some of the cancer cells on their road to distant metastasis [9]

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