Gene panel predicts low-risk prostate cancer fate

Researchers from the USA have identified a three-gene signature that can predict prostate cancer progression in low Gleason score tumors.

The team, led by Cory Abate-Shen (Columbia University Medical Center, New York), says the findings could help fulfill a “critical need” for a method to detect the minority of patients with low Gleason score tumors who go on to develop aggressive, lethal cancers.

The researchers established a set of 377 aging- and senescence-related genes, before using gene set enrichment analysis to identify 19 genes that were significantly up-regulated in indolent human prostate cancers and down-regulated in aggressive tumors in a mouse model of pre-invasive prostate cancer.

However, in a retrospective analysis of 131 human prostatectomy samples, the 19-gene signature could not stratify patients with sufficient accuracy.

Thus, using a decision tree model they identified a three-gene panel that accurately predicted patient survival in a cohort of 281 Swedish patients who were followed up for 30 years after treatment for localized prostate cancer.

They found that the panel – consisting of CDKN1A, FGFR1, and PMP22 – could consistently categorize patients with low Gleason score (6 and 7) into low- and high-risk groups and showed prognostic potential in all models and cohorts tested.

And, in biopsy material from 29 Gleason 6 patients who did not fail surveillance (ie, showed no signs of progression) over a minimum 10-year follow-up, there were robust and fairly uniform levels of the three gene products while in 14 Gleason 6 patients who failed surveillance there was reduced staining overall and much more variable levels of FGFR1, PMP22, and CDKN1A.

Abate-Shen and colleagues say that the particular three genes identified for their signature were somewhat surprising. While CDKN1A has previously been associated with cell senescence and prostate cancer progression, FGFR1 amplification has been linked to aggressive prostate cancer, while PMP22, which encodes a glycoprotein involved in the nervous system, has never been linked to the disease.

Reporting in Science Translational Medicine, the team explains that a recent push toward reduced screening and active surveillance for men with low-risk tumors means that those with more aggressive tumors may miss out on the opportunity for effective treatment.

The researchers believe that when combined with existing methods for clinical classification, such as urine biomarkers and blood messenger RNA levels, the gene panel could lead to a more effective use of active surveillance that better balances the risks for over- and under-treatment.

“Stratification of low Gleason score prostate cancer into indolent and aggressive subtypes may improve the landscape for effective prognosis by distinguishing those patients in need of expedited treatment interventions from those likely to remain clinically asymptomatic,” they conclude.

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