Background: Increased baseline body mass index (BMI) has been linked to poorer prostate cancer outcomes, including recurrence, reduced quality of life, and mortality (PMID: 21325564, 17211863). Herein, we sought to interrogate and validate the corresponding differences in tumor gene expression profiles of obese (Ob) vs. non-obese (N-Ob) pts with PC. Methods: In this IRB-approved retrospective study, eligibility criteria included histologically confirmed PC and available RNA sequencing results from treatment naïve primary prostate tissue from a CLIA-certified lab (either Tempus or Caris Life Sciences). Tempus cohort was used for interrogation and Caris for validation. Pts in each cohort were categorized into two groups: obese (BMI≥30) and non-obese (BMI<30). BMI at the time of diagnosis of PC was used for analysis. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Tempus cohort: n=60 (Ob =22, N-Ob=38); Caris cohort: n=50 (Ob=17, N-Ob=33). Both Tempus and Caris showed that Ob pts had an increased expression of the heme metabolism, androgen response, protein secretion, fatty acid, and bile metabolism pathways. N-Ob pts had a significantly higher expression of genes involved in the inflammation pathways (interferon-alpha & TNF alpha pathways). Normalized enrichment scores are reported in the table. Differential gene set expression analysis in Ob vs. N-Ob pts with PC. Conclusions: Our study showed an upregulation of distinct genomic pathways in Ob pts with prostate cancer. For example, Ob pts with PC have tumors that depend more on androgen signaling, and N-Ob pts' tumors express increased inflammatory pathway genes that promote PC growth, invasiveness, and metastasis. After external validation, these hypothesis-generating data may provide the rationale for personalized therapy in men with PC.

Positive NES = upregulation in Ob pts, and negative NES = downregulation in Ob pts.