January 24, 2018

Polygenic Score Predicts Age of Onset of Aggressive Prostate Cancer

Polygenic Score Predicts Age of Onset of Aggressive Prostate Cancer

January 24, 2018

NEW YORK (Reuters Health) - A new polygenic score can be used to predict an individual man's age of onset of aggressive prostate cancer - and thereby guide screening efforts - according to findings from the PRACTICAL Consortium.

"The most surprising result was how much better the genetic score was than family history in predicting age of onset for aggressive prostate cancer,” Dr. Tyler M. Seibert from University of California San Diego, in La Jolla, told Reuters Health by email. “We had expected the genetic score to be a good predictor, but we thought that family history might still offer complementary information to improve prediction.”

Because of high false-positive rates, most guidelines do not endorse universal screening for prostate-specific antigen (PSA), instead stressing the importance of individual patient risk factors in the decision whether to screen.

Dr. Seibert and colleagues used data from 31,747 men of European ancestry to develop a polygenic hazard score for predicting age-related risk of developing aggressive prostate cancer and then validated the score in an independent screening study. The findings were published online January 10 in The BMJ.

The hazard score, calculated from 54 single-nucleotide polymorphisms found to be associated with an increased risk of prostate cancer, performed well in predicting age at onset of aggressive prostate cancer in the development set.

When applied to the independent validation set, the hazard ratio for men with a score above the 98th percentile was 2.9-fold higher than the average risk of developing aggressive prostate cancer at a given age. Such high scores were separately associated with a 2.5-fold increased risk of any prostate cancer and a 3.0-fold increased risk of very aggressive prostate cancer.

Men with scores above the 50th percentile accounted for 76% of cases of aggressive prostate cancer, and the upper fifth accounted for 42% of such cases.

In the subset of patients with known family history status, family history alone did not predict age of onset of aggressive prostate cancer, although there was a trend toward prediction for any prostate cancer. Moreover, including family history did not improve the polygenic hazard score's predictions of aggressive prostate cancer or any prostate cancer.

“This study shows the tremendous potential of genetic scores to predict which men are at risk of developing aggressive prostate cancer at a young age,” Dr. Seibert said. “Currently, primary care doctors are expected to make a recommendation for each patient regarding screening - both whether to screen and at what age to start - but they are not given a lot of reliable, objective information to help inform that decision. The polygenic hazard score could help the primary care doctor provide a personalized decision for each patient based on that individual's own DNA.”

“Even in clinics where screening is common, most men are not offered testing until they are in their late 50s or older, so the men at risk in their 40s could be identified early by use of the genetic tool,” he said. “Other men will learn that their genetic risk is very low, which may make them more comfortable avoiding PSA screening.”

Dr. Laura Ottini from Sapienza University of Rome, in Italy, who recently used polygenic risk scores to predict breast and prostate cancer risks in male carriers of BRCA mutations, told Reuters Health by email, "These results add another piece of evidence that genetic prediction tools may be used to provide men and their physicians with more detailed information on their prostate cancer risk; thus they may aid prevention and screening decisions. The present tool can predict age at diagnosis of aggressive prostate cancer. This is of particular interest because age plays a critical role in clinical decisions for prostate cancer prevention.”

“We have a tool that in the near future may be used to guide physicians in taking decisions about who, whether, and when to screen for prostate cancer,” she said. “This is a further step towards precision prevention of cancer.”

Two of the authors have patent applications pending related to this work.


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