LAUSR

Introduction: Prostate cancer (PC) is a highly heterogeneous disease and can be either aggressive, requiring immediate treatment, or remain slow growing and even without treatment present no significant symptoms throughout the man’s life. Currently, there is an unmet need for new tools that can clearly distinguish indolent from aggressive PC in order to guide treatment decisions.PC is a highly heritable disease and so far, approximately 450 genomic regions associated with PC risk have been defined in genome-wide association studies. Most of these regions are however devoid of annotated genes and consequently the underlying mechanisms behind the associations are not easily elucidated. Accordingly, yet uncharacterized genes in PC-associated regions could be involved in PC development/progression. Methods: We quantified gene expression levels by Kallisto on total RNAseq data from fresh frozen prostate tissue samples from 134 localized PCs, 33 matched adjacent normal (AN) areas as well as 15 PC cell lines. Furthermore, we performed targeted RNAseq covering approximately seven million base pairs divided among 101 PC-risk associated regions (GWAS hits) for in-depth transcriptomic analyses in the same set of samples. HISAT and StringTie were used to identify novel transcripts (genes) with the criteria that a given gene had to have at least 10 reads in more than 50% of all samples to be included. Patient genotyping was performed on Illumina’s global screening array. Results: In totalRNA seq data we observed significant dysregulation of 10,256 genes (5,685 up- and 4,571 downregulated) between AN and localized PC, including upregulation of know PC-associated genes such as SIM2, PCAT7, TDRD1, and TFF3. Interestingly, we found a correlation between high transcription of TFF3 and high risk of biochemical recurrence (BCR) after radical prostatectomy and furthermore a trans-acting eQTL, the PC-risk associated SNP rs1938781. Here, heterozygote patients with the risk-allele had higher risk of BCR than patients homozygous for the reference allele, indicating a potential functional relationship between the PC risk-SNP and TFF3. Additionally, we detected 207 previously unannotated non-coding genes in the capture RNAseq data, where 148 (71.5%) were undetectable in the matched total RNAseq data indicating the existence of stably albeit lowly expressed genes in the genomic areas containing PC-risk SNPs. Citation Format: Jacob Fredsøe, Christa Haldrup, Iver Nordentoft, Benedicte Ulhøi, Michael Borre, Karina D. Sørensen. A novel targeted RNA sequencing approach for identification of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3307.