Abstract 3354: A gene expression signature of high serum cholesterol and prostate cancer outcomes

Abstract Statin use is associated with reduced risk of lethal prostate cancer potentially through effects on serum cholesterol. Using data from a prospective study with measured serum cholesterol among men subsequently diagnosed with prostate cancer, we developed a tumour gene expression score to reflect the pre-diagnosis serum cholesterol environment these tumours developed in, and applied this score to a separate study to examine the relationship with prostate cancer-specific outcomes. We identified 127 men with prostate cancer in the prospective Health Professionals Follow-up Study, whose prostate tumors underwent whole genome gene expression profiling. Pre-diagnosis serum cholesterol was measured a median of 3.3 years (IQR 1.5-4.8 years) prior to cancer diagnosis. We excluded men using statins either at time of blood draw for serum cholesterol measurement or at cancer diagnosis. Using tumor biopsy whole genome transcriptomic data from 232 prostate cancer patients treated with radiotherapy in Northern Ireland (NI), we generated the serum cholesterol score by summing z-score-transformed expression for each gene. PTEN status was measured using a published 50-gene transcriptional signature. Both signatures were dichotomized using the median cut-point. Age-adjusted and multivariable Cox regression analysis was used to compute HRs and 95% CI for associations of the cholesterol gene score with biochemical recurrence and metastasis risk. We identified in HPFS a set of 30 genes associated with pre-diagnostic serum cholesterol with a fold change ≥4 which included PTEN. In the NI Cohort, tumors with above median cholesterol scores had higher expression of the PTEN-null signature (p<0.001). Increased serum cholesterol tumor score was associated with higher Gleason grade (p<0.001); this relationship was stronger in PTEN-null tumours relative to PTEN-intact. Over a median follow-up of 11 years, 68 men experienced biochemical recurrence, and 28 developed metastasis. In age-adjusted analysis, patients with high serum cholesterol score had increased risk of recurrence (HR 1.84; 95% CI 1.13-2.99) and metastasis (HR 1.98; 95% CI 0.91-4.29), though the latter was not statistically significant. Associations with recurrence and metastasis were attenuated following further adjustment for Gleason score (HR 1.65; 95% CI, 0.98-2.77 and HR 1.49; 95% CI 0.66-3.35, respectively). Men with increased tumor gene expression of a serum cholesterol score, derived to reflect tumor development within a high serum cholesterol environment, were more likely to be diagnosed with a PTEN-null prostate cancer. These men had more aggressive prostate cancer at diagnosis and increased risk of recurrence, particularly men with PTEN-null disease. Our results support recent findings showing a reduced risk of PTEN-null prostate cancer in statin users, and inform our understanding of the potential role of serum cholesterol in prostate cancer etiology. Citation Format: Sarah Jane Winter, Sophia R. Halliday, Travis A. Gerke, Lorelei Ann Mucci, Konrad H. Stopsack, Gillian Prue, Suneil Jain, Emma H. Allott. A gene expression signature of high serum cholesterol and prostate cancer outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3354.