UCLA researchers in the Department of Human Genetics & Urology, have created a new statistical strategy to identify 1,178 new inherited biomarkers in treatment-naïve prostate cancer patients, that are able to predict how prostate cancer will progress.
BACKGROUND:
The Centers for Disease Control and Prevention estimate that new cancer diagnoses will rise by 22% in the next year. However, the associated chances of mortality for these newly diagnosed patients is predicted to continually drop over the next decade. This reduced mortality is largely attributed to increasingly high-quality health care, beginning with detection of the disease. In the past decade, the implementation of noninvasive cancer profiling (i.e. nuclear medicine, and intravital imaging) has risen, capturing patient cohorts that may have previously remained undetected. However, widespread use of these imaging techniques is impeded by high costs, and physicians only recommend scans when there are other signs of cancer progression. There is growing evidence to suggest that oncogenesis is driven by a combination of germline, environmental, and stochastic factors. The use of Genome-wide association studies (GWAS) has revealed several germline variants associated with elevated risk of cancer diagnosis, like BRCA2 in prostate cancer patients, a polymorphism that inhibits tumor suppressor function. Increasing evidence shows that prostate tumors can hijack epigenetic regulatory systems to silence tumor suppressors and modulate the tumor epigenome. This would suggest a role that common germline polymorphisms have in the development of aggressive prostate tumors. However, classical GWAS has failed in the identification of prostate tumor evasion mechanisms (loci), believed to be due to insufficiently large cohort sizes. However, there is a current need for the development of a rapid, non-invasive diagnostic tool that can survey a range of cancers and determine risk of progression: the most likely candidate for profiling in this manner is some form of GWAS.
INNOVATION:
UCLA researchers in the Department of Urology & Human Genetics created a new form of GWAS that merged germline and tumour information into a single statistical technique. This new approach was used to identify 1,178 biomarkers in treatment-naïve prostate cancer patients that are able to predict how prostate cancer will progress. The researchers assembled 589 patients with treatment-naïve prostate cancer and surveyed the direct link between germline and methylation to quantify associations with larger effect sizes than previous germline-survival analyses. DNA methylation is a common pathway of tumor initiation and progression, and allows aggressive growth of tumor tissue. The researchers were able to find a correlation between germline risk loci and tumor methylation, which they soon followed with epigenetic profiling. The researchers showed intricate crosstalk between the germline and epigenome of primary tumors, effectively creating a new way to predict where a cancer is going by studying the individual it arises and evolves in. This creates new germline biomarkers of aggressive disease to aid patient triage and optimize use of more invasive or expensive diagnostic assays.
POTENTIAL APPLICATIONS:
• The identification of risk factors for prostate cancer progression could lead to better use of non-invasive imaging techniques and the greater incidence of disease identification prior to progression.
• The identification of other risk factors associated with other forms of cancer.
• Non-invasive clinical risk-stratification tools
ADVANTAGES:
• Only profiling technique that has captured a vast group of prostate cancer biomarkers
• The ability to assess risk in prostate cancer progression
• Non-invasive, and extremely parallelizable
DEVELOPMENT-TO-DATE:
The GWAS profiling was performed on 589 treatment-naïve prostate cancer patients and identified 1,178 biomarkers specific for prostate cancer progression.
RELATED PAPERS:
Houlahan, K. E. et al., Genome-wide germline correlates of the epigenetic landscape of prostate cancer. Nat Med 25, 1615–1626 (2019).