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Background To determine the association between circadian pathway genetic variants and the risk of prostate cancer progression. Methods We systematically evaluated 79 germline variants in nine circadian pathway genes in a cohort of 458 patients with localized prostate cancer as the discovery phase. We then replicated the significant findings in another cohort of 324 men with more advanced disease. The association of each variant with prostate cancer progression was evaluated by a log-rank test and Cox regression. Results A single nucleotide polymorphism of the neuronal PAS domain protein 2 ( NPAS2 ) gene (rs6542993 A>T) was found to be associated with a significantly higher risk of disease progression in both localized ( P = 0.001) and advanced ( P = 0.039) prostate cancer cases. In silico analysis revealed decreased expression levels of NPAS2 in carriers of the T allele of rs6542993 compared with those carrying the A allele. Consistently, downregulation of NPAS2 expression was associated with more aggressive prostate cancer and poor progression-free survival (log-rank P = 0.002). Conclusions The NPAS2 rs6542993 polymorphism may be a promising biomarker, and may shed light on the pathways that govern prostate cancer progression. Electronic supplementary material The online version of this article (10.1186/s12935-019-0811-4) contains supplementary material, which is available to authorized users.

Autophagy is a complex process of autodigestion in conditions of cellular stress, and it might play an important role in the pathophysiology during carcinogenesis. We hypothesize that genetic variants of the autophagy pathway may influence clinical outcomes in prostate cancer patients. We genotyped 40 tagging single-nucleotide polymorphisms (SNPs) from 7 core autophagy pathway genes in 458 localized prostate cancer patients. Multivariate Cox regression was performed to evaluate the independent association of each SNP with disease progression. Positive findings were then replicated in an independent cohort of 504 advanced prostate cancer patients. After adjusting for known clinicopathologic factors, the association between ATG16L1 rs78835907 and recurrence in localized disease [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.54–0.90, P = 0.006] was replicated in more advanced disease (HR 0.78, 95% CI 0.64–0.95, P = 0.014). Additional integrated in silico analysis suggests that rs78835907 tends to affect ATG16L1 expression, which in turn is correlated with tumor aggressiveness and patient prognosis. In conclusion, genetic variants of the autophagy pathway contribute to the variable outcomes in prostate cancer, and discovery of these novel biomarkers might help stratify patients according to their risk of disease progression.

Apoptosis is an essential physiological process that controls many important biological functions. However, apoptosis signaling in relation to secondary metabolite biosynthesis in plants and fungi remains a mystery. The fungus Ganoderma lucidum is a popular herbal medicine worldwide, but the biosynthetic regulation of its active ingredients (ganoderic acids, GAs) is poorly understood. We investigated the role of 3′,5′-cyclic adenosine monophosphate (cAMP) signaling in fungal apoptosis and GA biosynthesis in G. lucidum. Two phosphodiesterase inhibitors (caffeine and 3-isobutyl-1-methylxanthine, IBMX) and an adenylate cyclase activator (sodium fluoride, NaF) were used to increase intracellular cAMP levels. Fungal apoptosis was identified by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and a condensed nuclear morphology. Our results showed that GA production and fungal apoptosis were induced when the mycelium was treated with NaF, caffeine, or cAMP/IBMX. Downregulation of squalene synthase and lanosterol synthase gene expression by cAMP was detected in the presence of these chemicals, which indicates that these two genes are not critical for GA induction. Transcriptome analysis indicated that mitochondria might play an important role in cAMP-induced apoptosis and GA biosynthesis. To the best of our knowledge, this is the first report to reveal that cAMP signaling induces apoptosis and secondary metabolite production in fungi.

Ultraconserved regions (UCRs) are DNA segments of longer than 200 bp in length that are completely conserved between human, rat, and mouse genomes. Recent studies have shown that UCRs are frequently located at fragile sites involved in cancers, and their levels of transcription can be altered during human tumorigenesis. We systematically evaluated 14 common single-nucleotide polymorphisms (SNPs) within UCRs in three cohorts of prostate cancer patients, to test the hypothesis that these UCR SNPs might influence clinical outcomes. Examination using multivariate analysis adjusted for known clinicopathologic factors found association between rs8004379 and recurrence in localized disease [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.41–0.91, P = 0.015], which was confirmed in the replication set (HR 0.70, 95% CI 0.51–0.96, P = 0.027). Remarkably, a consistent association of rs8004379 with a decreased risk for prostate cancer-specific mortality was also observed in the advanced prostate cancer patient group (HR 0.48, 95% CI 0.32–0.70, P < 0.001). Additional in silico analysis suggests that rs8004379 tends to affect NPAS3 expression, which in turn was found to be correlated with patient prognosis. In conclusion, our findings suggest that SNPs within UCRs may be valuable prognostic biomarkers for assessing prostate cancer treatment response and survival.

Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs) in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC) rs2707765 and rs497844, were significantly (p ≤ 0.009 and q ≤ 0.043) associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ≤ 0.003). Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer.

It is being debated whether prostate-specific antigen (PSA)-based screening effectively reduces prostate cancer mortality. Some of the uncertainty could be related to deficiencies in the age-based PSA cut-off thresholds used in screening. Current study considered 2779 men with prostate cancer and 1606 men without a cancer diagnosis, recruited for various studies in New Zealand, US, and Taiwan. Association of PSA with demographic, lifestyle, clinical characteristics (for cases), and the aldo–keto reductase 1C3 (AKR1C3) rs12529 genetic polymorphisms were analysed using multiple linear regression and univariate modelling. Pooled multivariable analysis of cases showed that PSA was significantly associated with demographic, lifestyle, and clinical data with an interaction between ethnicity and age further modifying the association. Pooled multivariable analysis of controls data also showed that demographic and lifestyle are significantly associated with PSA level. Independent case and control analyses indicated that factors associated with PSA were specific for each cohort. Univariate analyses showed a significant age and PSA correlation among all cases and controls except for the US-European cases while genetic stratification in cases showed variability of correlation. Data suggests that unique PSA cut-off thresholds factorized with demographics, lifestyle and genetics may be more appropriate for prostate cancer screening.

Accumulating evidence suggests the roles of glutamate metabotropic receptors (GRMs) in cancer, in addition to synaptic signalling. The present study assessed the associations of genetic variants in eight GRM genes with regard to risk and overall survival (OS) in 780 renal cell carcinoma (RCC) patients and controls. After adjustment for known risk factors, GRM5 rs7102764 T was associated with an increased risk of RCC (P = 0.006). Additional analysis has provided evidence that rs7102764 T was correlated with a higher expression of GRM5, which is consistently found to be upregulated in tumours, compared to normal tissues. Furthermore, the GRM3 rs701332 C, GRM4 rs2499707 T, and GRM4 rs4713742 T alleles were significantly associated with a poorer OS (P ≤ 0.030). The three loci were also observed to have strong cumulative effects on OS. Additional analysis has revealed a significant genotype‐expression correlation of rs2499707 T with increased GRM4 expression, which in turn leads to poorer OS in patients with RCC. GRMs might be involved in RCC development and progression, and genetic variants in GRMs might be promising biomarkers.