Abstract
BackgroundThe clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts.MethodsWe used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analyses were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SigCheck software.ResultsLow levels of TMEFF2 mRNA significantly (p < 0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9 ≤ HR ≥ 4.1; p ≤ 0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96 ≤ HR ≥ 4.28; p ≤ 0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p = 0.00017).ConclusionsThis study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa.
Highlights
The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease
We report that low TMEFF2 mRNA expression is associated with decreased disease free survival (DFS) in the Memorial Sloan Kettering Cancer Center (MSKCC) PCa dataset
Expression of TMEFF2 mRNA is significantly increased in the primary tumors of patients with PCa when compared to normal tissue, in multiple independent datasets (Fig. 1a)
Summary
The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Clinical variables including Gleason score, tumor stage, and PSA levels are used at the time of diagnosis to predict disease outcome [3, 4] These prognostic factors have limitations, resulting in significant rates of overtreatment, with associated comorbidities [5,6,7], and undertreatment, leading to disease progression and increased risk of PCa-specific mortality [8,9,10]. If shown to correlate with clinical behavior, these molecular subtypes could prove critical for the management and treatment of the disease Currently their prognostic value is not fully established, and a significant fraction of primary prostate cancers in the study could not be categorized within these molecular subsets, suggesting the existence of additional relevant molecular alterations
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