The impact of estimated tumour purity on gene expression-based drug repositioning of Clear Cell Renal Cell Carcinoma samples

Abstract

To find new potentially therapeutic drugs against clear cell Renal Cell Carcinoma (ccRCC), within drugs currently prescribed for other diseases (drug repositioning), we previously searched for drugs which are expected to bring the gene expression of 500 + ccRCC samples from The Cancer Genome Atlas closer to that of healthy kidney tissue samples. An inherent limitation of this bulk RNA-seq data is that tumour samples consist of a varying mixture of cancerous and non-cancerous cells, which influences differential gene expression analyses. Here, we investigate whether the drug repositioning candidates are expected to target the genes dysregulated in ccRCC cells by studying the association with tumour purity. When all ccRCC samples are analysed together, the drug repositioning potential of identified drugs start decreasing above 80% estimated tumour purity. Because ccRCC is a highly vascular tumour, attributed to frequent loss of VHL function and subsequent activation of Hypoxia-Inducible Factor (HIF), we stratified the samples by observed activation of the HIF-pathway. After stratification, the association between estimated tumour purity and drug repositioning potential disappears for HIF-activated samples. This result suggests that the identified drug repositioning candidates specifically target the genes expressed by HIF-activated ccRCC tumour cells, instead of genes expressed by other cell types part of the tumour micro-environment.

Selection of Optimal Candidates for Cytoreductive Nephrectomy in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Predictive Model Based on SEER Database

“…The first-line treatment for mccRCC is still systemic therapy including immunotherapy and targeted therapy (1,5). While it is common for mccRCC to develop drug resistance during systemic drug therapy (6)(7)(8)(9).…”

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

“…All genetic alterations described so far carry a superscripted number (Refs. [1–28]) that refers to the publication ID (Pub ID, first column in Table S4) of the literature review. Somatic mutations without a superscripted number were found in our analysis…”

“…ELST #6 demonstrated hypermethylation at cg15267345 within the CpG island of the VHL promoter compared to normal control tissue and other ELSTs. VHL promoter hypermethylation at cg15267345 has previously been described for sporadic renal clear cell carcinomas [17, 43]. However, because mRNA expression data were not available, it was not possible to show if the observed hypermethylation within the CpG island of the VHL promoter had a functional consequence and resulted in epigenetic silencing of VHL expression in ELST #6.…”

“…To evaluate the VHL promoter methylation status, we additionally analysed normal tissue pons ( n = 12; http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE90496). As evidence of epigenetic silencing, the VHL promoter was considered methylated if the beta value for probe cg15267345 within the CpG Island exceeded 0.2 as previously published [17, 18].…”

Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma

“…Alternatively, gene expression profiling was used to discover drug candidates repurposed for the treatment of ccRCC. Gene expression signatures of individual tumor samples have been used to personalize drug repurposing [18]. Koudijs et al collected tumor (n = 534) and matched normal (n = 72) samples from 530 ccRCC patients to create tumor signatures to connect these to drug signatures [19].…”