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Expressed prognostic biomarkers for primary prostate cancer independent of multifocality and transcriptome heterogeneity

Abstract

The majority of prostate cancer patients are diagnosed with multiple primary malignant foci. The distinct foci are exceptionally heterogeneous with regard to DNA mutations, but whether this is recapitulated at the transcriptome level remains unknown. In this study, inter- and intrafocal heterogeneity has been assessed by whole-transcriptome sequencing of 87 tissue samples from 23 patients with localized prostate cancer treated with radical prostatectomy. From each patient, multiple samples were taken from one or more malignant foci, in addition to one sample from benign prostate tissue. Transcriptomic profiles of different malignant foci from the same patient showed a similar level of heterogeneity as tumors from different patients. This applies to expression of genes, fusion genes, and somatic mutations. Within-patient pair-wise analyses identified expression patterns linked to ETS status and extraprostatic extension. A set of 62 genes were found with low intrapatient heterogeneity and high interpatient heterogeneity, retaining stable expression profiles across foci within the same patient. Among these, 16 genes are associated with biochemical recurrence in a separately published study and are therefore nominated as biomarkers with prognostic value regardless of which malignant focus is sampled. In conclusion, an extensive heterogeneity in multifocal prostate cancer is confirmed at the gene expression level. Diagnostic biomarkers were identified for ETS positive samples and samples from extraprostatic extensions. Finally, prognostic biomarkers independent of multifocal heterogeneity were found.

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Fig. 1: Principal component analysis shows heterogeneous gene expression levels between different clinicopathological categories and between different prostate tissue samples from the same patients.
Fig. 2: Expression of selected fusion genes with relevance to prostate cancer.
Fig. 3: Distribution of expression status for 2115 mutations in 64 malignant prostate cancer samples.
Fig. 4: Inter-patient and intra-patient heterogeneity scores.
Fig. 5: Genes differentially expressed in EPE vs. non-EPE malignant tissues from the same prostates.
Fig. 6: Genes differentially expressed in ETS positive vs. negative malignant tissues from the same prostates.

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Acknowledgements

The study was funded by the South-Eastern Norway Regional Health Authority (Project numbers 2017045, 2019016, and 2020063), the Research Council of Norway through its FRIPRO funding scheme (262529/F20 and Toppforsk-250993), the Norwegian Cancer Society (Grant number 208197), and a grant from Centre for Molecular Medicine Norway’s programme for networking. The study was granted secure storage and high-performance computation resources from NorStore and University of Oslo’s Services for Sensitive Data (NS9013S and p19, respectively). We are grateful to the individuals with prostate cancer and their families for contributing to this study.

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JMS handled the data, performed bioinformatics analyses, interpreted results, prepared figures, and tables, and wrote the report. BJ contributed to the bioinformatics analyses and managed the computational infrastructure. XZ performed survival analyses. SGK and KTC performed wet-lab validation. MB and UA performed histopathological evaluation. AS contributed to analyses on somatic mutations. KA had the clinical responsibility. AM, RAL, UA, KA, and RIS secured funding for the project. RIS conceptualized the research. All authors provided feedback on interpretation of results and on the report.

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Correspondence to Rolf I. Skotheim.

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Strømme, J.M., Johannessen, B., Kidd, S.G. et al. Expressed prognostic biomarkers for primary prostate cancer independent of multifocality and transcriptome heterogeneity. Cancer Gene Ther 29, 1276–1284 (2022). https://doi.org/10.1038/s41417-022-00444-7

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