Genetic Studies of Prostate Cancer Aggressiveness and Prognosis

Overview

Prostate cancer is the most common form of cancer and the leading cause of cancer-related deaths among men in Sweden. In 2021, over 10,000 men were diagnosed with prostate cancer, and 2,077 died from the disease. Patients diagnosed with early-stage prostate cancer often undergo treatment aimed at curing the disease. However, since the side effects of active treatment are significant, it is crucial to identify new markers for aggressive forms of prostate cancer to better determine who would benefit most from curative treatment. The investigators plan to conduct large-scale genetic studies using blood samples from men with prostate cancer. Specifically, the investigators will search for genetic markers associated with the development of more aggressive prostate cancer forms and markers for clinical progression. The clinical relevance of the identified genetic markers will be tested in a large population-based clinical prostate cancer study (the Stockholm-3 study). The overall goal of this research is to discover new genetic markers for prostate cancer that may lead to more personalized and precise prostate cancer diagnostics.

The investigators have the following specific aims: Aim 1. To perform GWAS and create GRS for aggressive PCa A GWAS for aggressive PCa will be performed in international cohorts comprising 29,896 PCa patients (19,185 with non-aggressive disease and 10,711 with aggressive disease). Using summary statistics from this GWAS in a supervised machine learning framework, The investigators aim to create a GRS predictive of aggressive PCa. Aim 2. To perform GWAS and create GRS for biochemical recurrence A GWAS for biochemical recurrence will be performed among patients who have undergone radical prostatectomy. Through international collaboration, 5,397 radical-operated patients will be available for assessment, among which biochemical recurrence occurred for 1,071 during follow-up. As in aim 1, supervised machine learning algorithms will be applied to the summary results from the GWAS to create a GRS for biochemical recurrence. Aim 3. To perform a TWAS for aggressive disease and biochemical recurrence The investigators will perform a multi-tissue TWAS for aggressive disease and biochemical recurrence. Genetic prediction models will be trained using gene expression data measured in 22 tissues from over 3,900 individuals. Through these prediction models, gene expression levels will be imputed in the aggressive (aim 1) and biochemical recurrence (aim 2) study population and explored for association with disease aggressiveness and biochemical recurrence. Aim 4. To assess the clinical translatability of GRS for aggressive disease and biochemical recurrence Using a large population-based Swedish clinical study of PCa detection, the clinical utility of GRS for aggressive disease and GRS for biochemical recurrence will be explored. In addition, a score based on rare pathogenic variants from 50 DNA repair genes will be assessed. The clinical utility of GRS will be established by comparing the added predictive performance of GRS above established predictive markers, PSA for detection, PSA, Gleason score, and TNM stage for a biochemical recurrence.