Simple SummaryProstate cancer is a global health burden. Multi-parametric magnetic resonance imaging is the recommended imaging modality for diagnosis. The recommended treatment differs based on tumor aggressiveness, typically assessed with the use of invasive techniques such as tumor biopsies. By studying the relationship between imaging characteristics and the genomic information obtained from tumor biopsies, it might be possible to detect aggressive tumor characteristics based solely on imaging, which could eventually be used to non-invasively inform on patient-tailored treatments. In this study, we extracted a large number of imaging features and found significant correlations between them and the aggressiveness of the tumor. We additionally investigated transcriptomic features (i.e., patterns of gene expression) associated with tumor aggressiveness and identified significant correlations with perfusion-related image features, highlighting a link between what is visible on the diagnostic images and the underlying genomic information of the tumors.AbstractProstate cancer (PCa) is a highly prevalent cancer type with a heterogeneous prognosis. An accurate assessment of tumor aggressiveness can pave the way for tailored treatment strategies, potentially leading to better outcomes. While tumor aggressiveness is typically assessed based on invasive methods (e.g., biopsy), radiogenomics, combining diagnostic imaging with genomic information can help uncover aggressive (imaging) phenotypes, which in turn can provide non-invasive advice on individualized treatment regimens. In this study, we carried out a parallel analysis on both imaging and transcriptomics data in order to identify features associated with clinically significant PCa (defined as an ISUP grade ≥ 3), subsequently evaluating the correlation between them. Textural imaging features were extracted from multi-parametric MRI sequences (T2W, DWI, and DCE) and combined with DCE-derived parametric pharmacokinetic maps obtained using magnetic resonance dispersion imaging (MRDI). A transcriptomic analysis was performed to derive functional features on transcription factors (TFs), and pathway activity from RNA sequencing data, here referred to as transcriptomic features. For both the imaging and transcriptomic features, different machine learning models were separately trained and optimized to classify tumors in either clinically insignificant or significant PCa. These models were validated in an independent cohort and model performance was used to isolate a subset of relevant imaging and transcriptomic features to be further investigated. A final set of 31 imaging features was correlated to 33 transcriptomic features obtained on the same tumors. Five significant correlations (p< 0.05) were found, of which, three had moderate strength (|r| ≥ 0.5). The strongest significant correlations were seen between a perfusion-based imaging feature—MRDIAmedian—and the activities of the TFs STAT6 (−0.64) and TFAP2A (−0.50). A higher-order T2W textural feature was also significantly correlated to the activity of the TF STAT6 (−0.58). STAT6 plays an important role in controlling cell proliferation and migration. Loss of the AP2alpha protein expression, quantified by TFAP2A, has been strongly associated with aggressiveness and progression in PCa. According to our findings, a combination of texture features extracted from T2W and DCE, as well as perfusion-based pharmacokinetic features, can be considered for the prediction of clinically significant PCa, with the pharmacokinetic MRDIAfeature being the most correlated with the underlying transcriptomic information. These results highlight a link between quantitative imaging features and the underlying transcriptomic landscape of prostate tumors.