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Following acute genotoxic stress, both normal and tumorous stem cells can undergo cell-cycle arrest to avoid apoptosis and later re-enter the cell cycle to regenerate daughter cells. However, the mechanism of protective, reversible proliferative arrest, "quiescence," remains unresolved. Here, we show that mitophagy is a prerequisite for reversible quiescence in both irradiated Drosophila germline stem cells (GSCs) and human induced pluripotent stem cells (hiPSCs). In GSCs, mitofission (Drp1) or mitophagy (Pink1/Parkin) genes are essential to enter quiescence, whereas mitochondrial biogenesis (PGC1α) or fusion (Mfn2) genes are crucial for exiting quiescence. Furthermore, mitophagy-dependent quiescence lies downstream of mTOR- and PRC2-mediated repression and relies on the mitochondrial pool of cyclin E. Mitophagy-dependent reduction of cyclin E in GSCs and in hiPSCs during mTOR inhibition prevents the usual G1/S transition, pushing the cells toward reversible quiescence (G0). This alternative method of G1/S control may present new opportunities for therapeutic purposes.

The mapping of around 100 single nucleotide polymorphism (SNP) susceptibility variants for prostate cancer represents a remarkable technological achievement driven by large multicentre collaborations and the lower cost of genomic technologies. The high degree of statistical certainty for each SNP locus in duplicate or even triplicate experiments provides a series of waypoints defining a genetic landscape that accounts for an estimated 33% of familial risk. A critical question addressed by Kearns et al [1] in this issue of European Urology is whether variant SNP status has relevance to patient outcome and clinical management beyond simple higher risk of disease incidence. The authors assess the relationship between prostate cancer upgrading in surgical and active surveillance (AS) cohorts and the 23 single SNP variants identified using the Collaborative Oncological Gene-environment Study iCOGS chip [2]. The surgical cohort consisted of 950 patients who were categorised into those who continued to have Gleason score (GS) 6 disease (nonupgraded) and those who had higher-grade disease (GS 7, upgraded) following surgical pathology. The AS cohort consisted of 205 low-risk patients initially diagnosed as GS 6 with PSA

Background Biomarkers are urgently required to dissect prostate cancer (PrCa) inter-patient disease heterogeneity to improve treatment and accelerate drug development. We analyzed blood mRNA expression arrays to identify metastatic castration resistant PrCa (CRPC) with poorer outcome. Methods Whole blood was collected into PAXgeneTM tubes from CRPC patients and PrCa patients selected for active surveillance (AS). In Stage I (derivation test-set) 69 CRPC patients were used as cases and 31 AS patients as controls; in Stage II (validation-set) 70 CRPC patients were evaluated. Whole blood RNA from patients in Stage I was hybridised to Affymetrix U133plus2 microarrays. Expression profiles were analysed using Bayesian Latent Process Decomposition (LPD) to identify RNA expression profiles associated with CRPC subgroups and prognosis. A reduced gene signature was then derived using Random Forest algorithm and later verified (Stage I) and validated (Stage II) by qRT-PCR studies. All p values were corrected for false discovery rate. Results LPD analyses of the mRNA expression data divided the evaluable patients in stage-I (n = 94) into 4 groups. LPD1 and LPD2 consisted almost entirely of CRPC patients (14/14; 17/18); LPD3 and LDP4 comprised similar proportions of CRPC patients (15/31; 12/21) vs controls (AS patients). LPD1 group patients had features of worse prognosis CRPC and poorer overall survival (OS) than CRPC patients in other LPD groups (p = 0.00007). A 9 gene signature (TERF2IP, TMCC2, SNCA, GABARAPL2, RIOK3, TFDP1, HMBS, SLC4A1, STOM) classified patients into this LPD1 group with a very low misclassification rate (1.2%). After verification of the signature by qRT-PCR, LPD1 membership was associated with worse OS in the derivation CRPC cohort (10.7 vs 25.6 months, p = 0.00001). Importantly, the prognostic value of this signature was confirmed in the validation CRPC cohort, where LPD1 membership was also associated to poor OS (9.2 vs 21.6 months, p = 0.001), and remained an independent prognostic factor in multivariable-analyses for both cohorts. The LPD1 signature was associated with bone marrow disruption (mobilization of early erythroid cells) and decreased immune response. Conclusion Gene expression signatures derived from whole Blood genome profiling identify CRPC patients with very poor outcomes. Disclosure All authors have declared no conflicts of interest.