A Molecular Signature Predictive of Indolent Prostate Cancer

Abstract

Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes—FGFR1, PMP22, and CDKN1A—that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.

Atg7 cooperates with Pten loss to drive prostate cancer tumor growth

“…Additionally, in some aggressive cancers, it is now known that autophagy is used to promote tumor survival and can contribute to therapeutic drug resistance (Guo et al 2013b). Given the often indolent nature of prostate cancer in many patients early in their course, in which the tumors may be present for many years before undergoing a more aggressive transformation, efforts to understand and modulate such a critical cellular survival mechanism may lead to larger long-term incremental improvements in disease control (Irshad et al 2013). To assess the importance of autophagy in prostate cancer, we generated a new GEMM of prostate cancer driven by conditional prostate-specific deficiency in the Pten tumor suppressor without and with ablation of the essential autophagy gene Atg7 (Nkx3.1…”

Genomic Predictors of Outcome in Prostate Cancer

“…[54,60,61]. A few studies investigated TURP tissue to predict the outcome of men undergoing conservative treatment [51,62,63].…”

“…The design of discovery studies included several approaches: single-and multicenter studies and correlation of gene panel data to outcomes of the full cohort or selected subgroups [42,51,52,57,58,62] or a case-control population selected on a particular outcome [53,59,60,63]. All except one study reported that the applied expression panel offered significant prognostic information in the particular study cohort.…”

“…Studies have utilized different methodological approaches to assess the value of genomic tests. These approaches included traditional statistical methods (survival analyses, multivariable models with other clinicopathologic variables, and receiver operating characteristic analysis) [42,[51][52][53]59,60,[62][63][64]. In some studies, results from expression panels were combined with other variables or a nomogram to determine if genomic data added prognostic information above the baseline models [54,57,58,61,65].…”

Copy number alteration burden predicts prostate cancer relapse

“…Tumor-derived RNA signatures have been developed that are associated with the risk of death from prostate cancer, some of which are now in clinical use (7)(8)(9). These molecular signatures were generally developed from tumor samples obtained at surgery by examining their association with outcome after surgery, then subsequently evaluated in the preoperative setting using biopsies as the source of tumor RNA.…”