Dataset Information

A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

ABSTRACT:

Background

Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer.

Methods

The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels was applied in the analyses. Hypoxic fraction from pimonidazole immunostained whole-mount and biopsy sections was used as reference standard for hypoxia.

Results

The gene score was correlated with pimonidazole-defined hypoxic fraction in whole-mount sections, and the two parameters showed almost equal association with clinical markers of tumour aggressiveness. Based on the gene score, incorrect classification according to hypoxic fraction in whole-mount sections was seen in one third of the patients. The incorrect classifications were apparently not due to intra-tumour heterogeneity, since the score had low heterogeneity compared to pimonidazole-defined hypoxic fraction in biopsies. The score showed prognostic significance in uni-and multivariate analysis in independent cohorts.

Conclusions

Our signature from the index lesion reflects tumour hypoxia and predicts prognosis in prostate cancer, independent of intra-tumour heterogeneity in pimonidazole-defined hypoxia.

SUBMITTER: Salberg UB

PROVIDER: S-EPMC9296675 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

Salberg Unn Beate UB Skingen Vilde Eide VE Fjeldbo Christina Sæten CS Hompland Tord T Ragnum Harald Bull HB Vlatkovic Ljiljana L Hole Knut Håkon KH Seierstad Therese T Lyng Heidi H

British journal of cancer 20220324 2

<h4>Background</h4>Gene signatures measured in a biopsy have been proposed as hypoxia biomarkers in prostate cancer. We assessed a previously developed signature, and aimed to determine its relationship to hypoxia and its heterogeneity within the dominant (index) lesion of prostate cancer.<h4>Methods</h4>The 32-gene signature was assessed from gene expression data of 141 biopsies from the index lesion of 94 patients treated with prostatectomy. A gene score calculated from the expression levels w ...[more]

PMID: 35332267

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Project description:Cancer-associated fibroblasts (CAFs), the central players in the tumor microenvironment (TME), can promote tumor progression and metastasis via various functions. However, the properties of CAFs in prostate cancer (PCa) have not been fully assessed. Therefore, we aimed to examine the CAF characteristics in PCa and construct a CAF-derived signature to predict PCa prognosis. CAFs were identified using single-cell RNA sequencing (scRNA-seq) data from 3 studies. We performed the FindAllMarkers function to extract CAF marker genes and constructed a signature to predict the biochemical relapse-free survival (bRFS) of PCa in the Cancer Genome Atlas (TCGA) cohort. Subsequently, different algorithms were applied to reveal the differences of the TME, immune infiltration, treatment responses in the high- and low-risk groups. Additionally, the CAF heterogeneity was assessed in PCa, which were confirmed by the functional enrichment analysis, gene set enrichment analysis (GSEA), and AUCell method. The scRNA-seq analysis identified a CAF cluster with 783 cells and determined 183 CAF marker genes. Cell-cell communication revealed extensive interactions between fibroblasts and immune cells. A CAF-related prognostic model, containing 7 genes (ASPN, AEBP1, ALDH1A1, BGN, COL1A1, PAGE4 and RASD1), was developed to predict bRFS and validated by 4 independent bulk RNA-seq cohorts. Moreover, the high-risk group of the signature score connected with an immunosuppressive TME, such as a higher level of M2 macrophages and lower levels of plasma cells and CD8+ T cells, and a reduced reaction rate for immunotherapy compared with low-risk group. After re-clustering CAFs via unsupervised clustering, we revealed 3 biologically distinct CAF subsets, namely myofibroblast-like CAFs (myCAFs), immune and inflammatory CAFs (iCAFs) and antigen-presenting CAFs (apCAFs). In conclusion, the CAF-derived signature, the first of its kind, can effectively predict PCa prognosis and serve as an indicator for immunotherapy. Furthermore, our study identified 3 CAF subpopulations with distinct functions in PCa.

Dataset Information

A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

Background

Methods

Results

Conclusions

Publications

A prognostic hypoxia gene signature with low heterogeneity within the dominant tumour lesion in prostate cancer patients.

Similar Datasets

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