Grant Number:	2R01CA241410-06 Interpret this number
Primary Investigator:	Witte, John
Organization:	Stanford University
Project Title:	Precision Prostate Cancer Screening with Genetically Adjusted Prostate-Specific Antigen Levels
Fiscal Year:	2025

Abstract Prostate-specific antigen (PSA) screening is controversial because it can lead to overdiagnosis and overtreatment of prostate cancer when individuals have high PSA levels for reasons other than aggressive disease. It is thus important to ask the question how PSA screening can be improved. Preliminary evidence from our team suggests that the incorporation of genetic factors into PSA screening decisions has tremendous potential. During the initial funding period of this project, we have had great success showing that accounting for genetic factors that impact constitutive, non-cancer PSA levels results in a test that ascertains more clinically relevant, aggressive disease. In parallel, we have shown that genetic factors for PSA can also be used to improve polygenic risk scores (PRS) for prostate cancer. Existing PRS are strongly predictive of prostate cancer risk, but they do not specifically predict aggressive disease because they were largely developed in men with PSA screen- detected, lower-risk disease. We have initial results demonstrating that removing PSA genetic factors from prostate cancer PRS makes the PRS more predictive of aggressive disease. Additional studies are needed to clarify how best to adjust for PSA genetics to improve screening, to develop a prostate cancer PRS that is even more predictive of aggressive disease by removing additional PSA variants, and to assess the clinical utility of these tools. In this renewal, we propose to tackle these outstanding imperatives with a comprehensive project leveraging data from 13 studies ranging from large-scale biobanks to unique clinical populations (N > 500K). In Aim 1, we will further advance our understanding of PSA genetics by identifying novel rare and common PSA variants and undertaking functional studies of epigenomic features and single-cell expression quantitative loci. We will then use this information to develop more accurate and personalized genetic adjustment of PSA levels. In Aim 2, we will develop a new PRS for prostate cancer aggressiveness by filtering out PC risk variants that are also associated with non-cancer PSA. We will first remove PSA variants from the prostate cancer PRS based on statistical significance. Then we will develop and apply a novel hierarchical modeling genome-wide approach that incorporates PSA associations and functional information. In Aim 3, we will determine the clinical utility of incorporating genetically adjusted PSA levels and the PRS for aggressive prostate cancer into validated risk calculators for biopsy outcomes (higher grade disease) and prostate cancer active surveillance upgrading. We will also investigate the relationships between genetically adjusted PSA, the aggressive prostate cancer PRS, and lethal prostate cancer. These models will allow us to assess the benefit of incorporating genetic information into decisions about frequency of screening, escalation to prostate biopsy, and selection of active surveillance following diagnosis. Our renewal aims in aggregate are promising toward reducing PSA screening harms while improving screening benefits and predicting risk of clinically important disease. In translation, clinicians and patients could make more informed decisions, reducing unnecessary procedures and improving outcomes.