Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer

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Published: 25 Feb 2022
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Dr Meghana Pagadala - University of California San Diego, San Diego, USA

Dr Meghana Pagadala speaks to ecancer about evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort.

Initially, she talks about the background and the methodology of the study.

She says the objective of the study was to determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of fatal or metastatic prostate cancer in a diverse population.

Dr Pagadala further talks about the results from the study and the impact of these results on the future treatment of prostate cancer patients.

In this study we aimed to validate a polygenic hazard score, PHS290, in one of the largest ever cohorts which is the Million Veteran Program. Specifically what we found is that the PHS290 was associated with metastatic prostate cancer and death from prostate cancer, even when we accounted for family history and ancestry, which was very promising.

Furthermore, we found that PHS290 helped to stratify prostate cancer risk in non-European ancestry groups, including African, Hispanic and Asian ancestry groups.

What was the methodology?

For the study what we did is we built a genetic risk score that was previously developed by the senior author, Tyler Seibert, and others. We built it in the Million Veteran Program and then we ran a Cox proportional hazards analysis with three prostate cancer clinical outcomes. So this was whether you were diagnosed with prostate cancer at any point, whether you were diagnosed with metastatic prostate cancer or whether you died from prostate cancer, that was based on the National Death Index. This was based in the Million Veteran Program which is a programme that has genetic and also clinical information for veterans over the US hospitals.

What were the key results?

The key results were that we found that this PHS290 polygenic hazard score, which was developed to specifically predict age-specific prostate cancer risk, helped to stratify prostate cancer risk in the Million Veteran Program and also stratify risk of dying from prostate cancer. So this was really critical because we were able to identify high risk prostate cancer patients.

Furthermore, because the Million Veteran Program is one of the most diverse patient cohorts we found specifically that PHS290 helped to stratify risk of dying from prostate cancer in individuals of African ancestry.

How can these results impact the future treatment of prostate cancer?

We hope that the PHS290 can be used to help men decide if they want to get screened for prostate cancer or implement lifestyle interventions to help mitigate their risk of dying from prostate cancer. Also we hope that this analysis will help to spur more analyses of prostate cancer risk in more diverse populations, specifically in African American individuals because they do have a higher incidence and mortality rate for prostate cancer.

What’s next for the study?

This study was just the tip of the iceberg for us and it was a validation study of the PHS290. We hope to continue to improve upon this score and optimise it, also to develop the score and optimise it in admixed individuals and improve our ancestry assignments in the Million Veteran Program.

We also hope to incorporate other information such as Gleason score and PSA screening to continue to improve our stratification tool.