Obesity, metabolic health and aggressive prostate cancer; an integrated analysis of imaging and genomics data

Abstract

Introduction:
Prostate cancer is the second most diagnosed male cancer globally. Despite relatively high survival rates, a subset of men progress to advanced disease, which, due to high incidence rates, makes prostate cancer the fifth leading cause of cancer mortality in men worldwide. Obesity and poor metabolic health have been implicated in advanced prostate cancer risk as well as poor prostate cancer outcomes, though the exact mechanisms are not yet fully understood. The purpose of this research was to examine the mechanistic underpinnings of potentially modifiable metabolic factors which have been postulated to influence the aggressiveness of prostate cancer. The primary hypothesis is that men exhibiting features of poor metabolic health such as elevated visceral adipose tissue and altered cholesterol metabolism will have more aggressive prostate cancer and poorer prostate cancer-specific outcomes.

Methods:
In chapter 3, the association of adipose tissue quantity and radiodensity, measured from radiation planning computed tomography scans, with prostate cancer-specific outcomes was examined in a group of Northern Irish prostate cancer patients. Next, bioinformatics approaches and statistical analysis techniques were applied to existing studies of prostate cancer integrating clinical data and follow up with molecular data including tumour transcriptomics. Across these datasets, single gene and pathway level abnormalities in tumour intrinsic cholesterol metabolism were examined in association with tumour aggressiveness and outcomes in chapter 4. In chapter 5, to understand possible mechanisms through which hypercholesterolaemia is linked with more aggressive prostate cancer, a tumour gene signature reflecting high pre-diagnosis serum cholesterol levels developed in a large prospective cohort was examined in relation to prostate cancer aggressiveness and outcomes in a number of validation settings. In chapter 6, using metabolomics data, alterations in lipid metabolites were examined by poor prognosis characteristics such as obesity and circulating tumour cell count in a group of metastatic prostate cancer patients.

Results:
High waist circumference, reflecting abdominal obesity was associated with increased odds of high-grade prostate cancer, but elevated quantities of abdominal subcutaneous and visceral adipose tissue were not associated with prostate cancer aggressiveness, or outcomes when considered separately. Elevated quantities of periprostatic adipose tissue, the fat depot that encompasses the prostate was associated with increased likelihood of high-grade disease, but not with prostate cancer-specific outcomes or all-cause mortality. Upon exploratory gene set enrichment analysis using tumour transcriptomic data, we found that men with high periprostatic fat had enrichment of the KEGG adipocytokine signalling pathway, offering paracrine signalling as a potential mechanism linking high pelvic fat quantity with aggressive prostate cancer. These findings suggest that reducing visceral fat quantity could be beneficial in the prevention of aggressive prostate cancer.
We identified genes involved in cholesterol biosynthesis such as LBR and SQLE associated with increased odds of high-grade prostate cancer. However, following creation of a gene score, thought to reflect the upregulation of this pathway, we found that cholesterol biosynthesis was downregulated among men with worse outcomes.
Using a tumour gene score intended to reflect serum cholesterol levels, we found inconsistent associations between this score with tumour aggressiveness and outcomes across the patient studies examined. Despite this, our serum cholesterol score was elevated among men reported to have high serum cholesterol, supporting its intended purpose.

Conclusion:
Overall, our work provides further support for a role for visceral adiposity and dysregulated cholesterol metabolism, two potentially modifiable lifestyle factors in prostate cancer aggressiveness and outcomes. Our work provides support for elevated periprostatic adipose tissue in driving tumour aggressiveness, in addition to providing biological rationale for this association through our identification of elevated adipocytokine signalling in the tumours of men with periprostatic obesity. Several genes involved in tumour cholesterol biosynthesis were implicated in tumour aggressiveness. One of these genes, SQLE, has also been identified by other studies to be associated with lethal prostate cancer, and is inhibited by the antifungal drug terbinafine raising the possibility of drug repurposing to improve prostate cancer outcomes. Together, our findings support the importance of maintaining healthy body weight and cholesterol levels, particularly among men diagnosed with prostate cancer.

Theis embargoed until 31st Jul 2027

Date of Award	Jul 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Emma Allott (Supervisor), Suneil Jain (Supervisor) & Gillian Prue (Supervisor)