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Novel polygenic hazard score predicts age at onset of aggressive prostate cancer

Stephen Padilla
25 Jan 2018

Researchers have developed a new polygenic hazard score, which has been validated by an independent dataset, for assessing personalized genetic risk that can predict age at onset of aggressive prostate cancer, reports a study.

“Moreover, the score can predict the utility of PSA [prostate-specific antigen] testing for an individual man,” researchers said.

The independent validation set showed that the hazard score calculated from 54 single nucleotide polymorphisms robustly predicted of age at diagnosis of aggressive cancer (z, 11.2; p<10-16). The hazard ratio for aggressive cancer was 2.9 (95 percent CI, 2.4‒3.4) when comparing men in the validation set with high scores (>98th centile) to those with average scores (30th‒70th centile). [BMJ 2018;360:j5757]

In a combined model, prediction of aggressive prostate cancer onset did not improve with the inclusion of family history. Polygenic hazard score performance was still high when family history was considered. In addition, the positive predictive value of PSA screening for aggressive prostate cancer improved with increasing polygenic hazard score.

“Genetic information can guide the decision of whether an individual patient needs prostate cancer screening,” researchers said. [Sci Transl Med 2010;2:62ps55]

“The polygenic hazard score described here represents a personalized genetic assessment of a man’s age-related risk that could inform both whether and when to order screening tests… As the score is representative of a man’s fixed genetic risk, it can be calculated once … and substantially inform the decision of whether he should undergo prostate cancer screening,” they added.

Previous studies have shown that genetic features can predict prostate cancer risk, according to researchers. [Nat Genet 2013;45:385-391,e1-2; J Intern Med 2012;271:353-365; Sci Transl Med 2010;2:62ps55; Br J Cancer 2011;104:1656-1663; Cancer Epidemiol Biomarkers Prev 2015;24:1121-1129; Genet Med 2015;17:789-795; Future Oncol 2014;10:1679-1694]

Examining the genotypic features could provide greater understanding into biological rationales for the association with prostate cancer, they added.

In the current study, all consortium participants of European ancestry with known age, prostate cancer status and quality assured custom array genotype date were included. A total of 31,747 men comprised the development dataset, while 6,411 men were involved in the validation dataset.

Genotype, prostate cancer status and age were analysed to select single nucleotide polymorphisms associated with diagnosis. These polymorphisms were fused into a survival analysis to examine their effects on age at diagnosis of aggressive prostate cancer (ie, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3‒T4, PSA concentration ≥10 ng/L, nodal metastasis, distant metastasis).

Researchers then applied the final model to an independent dataset containing genotype and PSA screening data, and calculated the hazard score to test prediction of survival free from prostate cancer.

“This genetic risk model might play a role in guiding decisions about whether and when to screen for prostate cancer,” they said. “Investigation into the relation between the score and early midlife PSA testing is warranted.”

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