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Abstract
Only a limited number of studies have explored the possible associations between tumour grade and mutated genes in clear cell renal cell carcinoma (ccRCC), and we set out to investigate this further using a multiple sampling and next generation sequencing (NGS) approach in a series of ccRCCs. Multiple regions were sampled from formalin-fixated paraffin-embedded ccRCC tumour blocks from seven patients. In 27 samples from six patients, we performed targeted NGS using a custom 42-gene panel based on the most frequently mutated genes in ccRCC reported in public databases. In four samples from the seventh patient, we performed whole exome sequencing (WES) and array comparative genomic hybridisation for detection of copy number variants (CNVs). Mutated genes and the tumour grades of the samples in which they had been identified were compared both within and between all individual tumours. CNVs were compared across all samples from patient 7. We identified clear genetic heterogeneity within and across tumours, but VHL mutations were seen in all patients. Looking across all samples, we identified eleven genes that were only mutated in samples with one particular tumour grade. However, these genes were never mutated in all samples with that tumour grade. Increasing chromosomal instability corresponded with increasing tumour grade, but we observed minimal association between tumour grade and total mutational load in the WES data. Our study confirms the genetic heterogeneity and tumour grade heterogeneity of ccRCC. Although a relatively small number of samples was analysed, genes were identified that could potentially be specific, though insensitive, markers of higher ccRCC tumour grades.
Highlights
Kidney cancer is the 14th most common cancer worldwide, with clear cell renal cell carcinoma accounting for 70% of total cases in adult patients (Bray et al, 2018; Moch et al, 2016)
The 42 genes of our targeted panel were selected based on their high mutational frequency in clear cell renal cell carcinoma (ccRCC), as described in several studies and in The Cancer Genome Atlas Network database (Dalgliesh et al, 2010; Duns et al, 2012; Forbes et al, 2011; Network, 2013; Pena-Llopis et al, 2012; Sato et al, 2013), and from genes associated with the VHL/HIF pathway and the (PI3K)-AKT-MTOR pathway in ccRCC (Sato et al, 2013)
For the six patients subjected to targeted sequencing, most mutations were observed in the two most frequently mutated genes in ccRCC, e.g. VHL and PBRM1 (Forbes et al, 2017; Network, 2013)
Summary
Kidney cancer is the 14th most common cancer worldwide, with clear cell renal cell carcinoma (ccRCC) accounting for 70% of total cases in adult patients (Bray et al, 2018; Moch et al, 2016). Tumour morphology has been shown to correlate with both tumour progression and prognosis (Dagher et al, 2017), the prognostic value of mutational profiling in ccRCC is less clear. The mutation rank system was introduced, in which mutations were scored and ranked by their functional impact based on in silico analysis using gene variant predictor tools (Gonzalez-Perez et al, 2013). Using this ranking, some genes were found to harbour more frequent mutations with higher predicted functional impact compared to other genes, and were referred to as cancer driver genes.
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