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A five-gene expression signature to predict progression in T1G3 bladder cancer

ABSTRACT: To analyze the gene expression profiles of progressive and non-progressive T1G3 bladder cancer (BCa) patients in order to develop a gene expression signature to predict tumour progression. Multicenter, retrospective study of formalin-fixed paraffin embedded (FFPE) tissue samples from 96 T1G3 BCa patients who underwent a transurethral resection. Patients with concomitant CIS were excluded. Global gene expression patterns were analyzed in 21 selected samples from progressive and non-progressive T1G3 BCa patients using microarrays. Expression levels of 94 key genes selected from microarrays and from the literature were studied by quantitative PCR in an independent cohort of 75 samples from progressive and non-progressive T1G3 BCa patients. Univariate logistic regression was used to identify individual predictors. Progressive and non-progressive T1G3 BCa patients show different gene expression patterns. Identification of new genes associated with a high probability of tumour progression in combination with a robust, easy-to-use and reliable algorithm may contribute to tailor treatment and surveillance strategies in these patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57813 | GEO | 2016/07/29

SECONDARY ACCESSION(S): PRJNA248142

REPOSITORIES: GEO

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Project description:Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Estrogen receptor alpha (ERa) is overexpressed in 70% of diagnosed BCa patients and androgen receptor (AR) is overexpressed in 80-90% of diagnosed PCa patients. Thus, BCa and PCa patients are given therapy that reduces hormone levels or directly blocks HR activity; but most patients eventually develop treatment resistance. 15-30% of BCa patients and ≥ 30% of PCa patients that acquire treatment resistance develop tumors enriched in cancer cells with low or no HR accumulation. Furthermore, 15-20% of BCa patients and 10-20% of PCa patients are intrinsically HR-negative (HR-), and thus, have intrinsic resistance to therapy. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERa and AR mRNA in HR-positive (HR+) BCa and PCa cell lines. Additionally, we had identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells, to promote HR-independent survival and tumorigenicity. Methods: To identify changes in global gene expression we performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in BCa and PCa cell lines. We also compared our gene expression data with publicly available data sets from hormone receptor-independent sublines. Finally, we performed Ingenuity Pathway Analysis (IPA) to identify signaling pathways encode by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in hormone receptor-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired treatment resistance. We also assessed HR- cell line viability in response verteporfin, an FDA approved therapy for macular degeneration known to target p62, and we found that verteporfin is cytotoxic for HR- cells lines. Conclusions: Taken together, our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic hormone receptor-independent BCa and PCa.

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A five-gene expression signature to predict progression in T1G3 bladder cancer

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