Development of an autophagy-related gene expression signature for prognosis prediction in prostate cancer patients.
ABSTRACT: BACKGROUND:Prostate cancer (PCa) is one of the most prevalent cancers that occur in men worldwide. Autophagy-related genes (ARGs) may play an essential role in multiple biological processes of prostate cancer. However, ARGs expression signature has rarely been used to investigate the association between autophagy and prognosis in PCa. This study aimed to identify and assess prognostic ARGs signature to predict overall survival (OS) and disease-free survival (DFS) in PCa patients. METHODS:First, a total of 234 autophagy-related genes were obtained from The Human Autophagy Database. Then, differentially expressed ARGs were identified in prostate cancer patients based on The Cancer Genome Atlas (TCGA) database. The univariate and multivariate Cox regression analysis was performed to screen hub prognostic ARGs for overall survival and disease-free survival, and the prognostic model was constructed. Finally, the correlation between the prognostic model and clinicopathological parameters was further analyzed, including age, T status, N status, and Gleason score. RESULTS:The OS-related prognostic model was constructed based on the five ARGs (FAM215A, FDD, MYC, RHEB, and ATG16L1) and significantly stratified prostate cancer patients into high- and low-risk groups in terms of OS (HR?=?6.391, 95% CI?=?1.581- 25.840, P? 7 than??? 7 (P?=?0.015). In addition, the DFS-related prognostic model was constructed based on the 22 ARGs (ULK2, NLRC4, MAPK1, ATG4D, MAPK3, ATG2A, ATG9B, FOXO1, PTEN, HDAC6, PRKN, HSPB8, P4HB, MAP2K7, MTOR, RHEB, TSC1, BIRC5, RGS19, RAB24, PTK6, and NRG2), with AUC of 0.85 (HR?=?7.407, 95% CI?=?4.850-11.320, P?
Project description:Autophagy is a catabolic cellular process used for degradation of cytoplasmic organelles and preservation of cell viability. In this study we aimed to analyse the level of autophagy markers in benign and malignant prostate tissue and to evaluate the prognostic properties for patients with prostate cancer (PCa).LC3b expression was significantly upregulated in PCa, especially in metastatic and castration-resistant PCa samples compared to benign prostate tissue (p<0.001). Evaluation of expression in malignant radical prostatectomy specimens revealed an inverse association with preoperative serum PSA levels (p=0.02) and Gleason Score (p=0.07). LC3b immunoreactivity was identified as a novel predictor of PCa specific death after radical prostatectomy, independent of Gleason score, tumour stage, and surgical margin status in a multivariable cox regression analysis (hazard ratio 0.09, 95% confidence interval 0.01-0.69, p=0.021). A significant association of ATG-5 and Beclin 1 with LC3b expression could be noticed (p<0.001), but no link with other clincopathologic parameters was observed.A Tissue microarray containing 468 formalin-fixed, paraffin-embedded prostate tissue cores was stained immunohistochemically for major autophagy proteins LC3b, ATG5 and Beclin 1. Immunoreactivity was semiquantitatively scored and correlated with pathologic and clinical parameters, including tumour stage, Gleason score, preoperative PSA level, biochemical recurrence rate and survival. The median clinical follow-up was 132 months.LC3b was significantly overexpressed in malignant compared to benign prostate tissue. However, positive LC3b immunoreactivity in PCa, as a marker of increased autophagy, was independently associated with a reduced disease-specific mortality.
Project description:<h4>Background</h4>Serine-arginine protein kinase 1 (SRPK1) has been implicated in prostate cancer (PCa) progression. However, its prognostic value and association with ERG and PTEN expression, two of the most common genetic alterations, have not been explored fully.<h4>Objective</h4>We assessed the prognostic value of SRPK1 in association with ERG and PTEN in a cohort of patients managed nonsurgically by androgen deprivation therapy (ADT) for advanced disease.<h4>Design setting and participants</h4>The study cohort consisted of men diagnosed with PCa by transurethral resection of the prostate (TURP; <i>n</i> = 480). The patients were divided into three main groups: incidental (patients with Gleason score [GS] ≤7 with no prior ADT), advanced (patients with GS ≥8 with no prior ADT), and castrate-resistant PCa (patients with prior ADT).<h4>Outcome measurements and statistical analysis</h4>A total of 480 TURP samples were assessed by immunohistochemistry for SRPK1, ERG, and PTEN, and results were correlated with Gleason grade group (GG), overall survival (OS), and PCa-specific mortality (PCSM).<h4>Results and limitations</h4>High SRPK1 expression was noted in 105/455 (23%) available patient cores. Expression of SRPK1 was associated with Gleason grade grouping (<i>p</i> < 0.0001) with high expression detected in 22/74 (33%) with GG 5. High SRPK1 was not associated with ERG positivity (<i>p</i> = 0.18) but was significantly associated with PTEN intensity (<i>p</i> = 0.001). High SRPK1 was associated with OS (hazard ratio [HR] 1.99; confidence interval [CI]: 1.57-2.54, <i>p</i> < 0.0001) and PCSM (HR 1.64; CI: 1.19-2.26, <i>p</i> < 0.002). Adjusting for Gleason score, patients with high SRPK1 and negative PTEN had the worst clinical outcome for both OS and PCSM compared with other patients (<i>p</i> < 0.0001, HR: 3.02; CI: 1.87-4.88 and HR: 6.40, CI: 3.19-12.85, respectively).<h4>Conclusions</h4>High SRPK1 is associated with worse OS and PCSM. Moreover, patients with high SRPK1 expression and loss of PTEN had the worst clinical outcome for OS and cancer-specific mortality. Combined status of SRPK1 and PTEN may provide added value in stratifying patients into various prognostic groups.<h4>Patient summary</h4>The expression of serine-arginine protein kinase 1 (SRPK1) combined with PTEN has a significant prognostic role in prostate cancer patients. Patients with high SRPK1 expression and negative PTEN had the worst clinical outcome for overall survival and cancer-specific mortality.
Project description:Abnormal autophagy is closely related to the development of cancer. Many studies have demonstrated that autophagy plays an important role in biological function in clear cell renal cell carcinoma (ccRCC). This study aimed to construct a prognostic signature for ccRCC based on autophagy-related genes (ARGs) to predict the prognosis of ccRCC. Differentially expressed ARGs were obtained from ccRCC RNA-seq data in The Cancer Genome Atlas (TCGA) database. ARGs were enriched by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The prognostic ARGs used to construct the risk score models for overall survival (OS) and disease-free survival (DFS) were identified by Cox regression analyses. According to the median value of the risk score, patients were divided into a high-risk group and a low-risk group. The OS and DFS were analyzed by the Kaplan-Meier method. The predictive accuracy was determined by a receiver operating characteristic (ROC) curve analysis. Additionally, we performed stratification analyses based on different clinical variables and evaluated the correlation between the risk score and the clinical variables. The differentially expressed ARGs were mainly enriched in the platinum drug resistance pathway. The prognostic signatures based on 11 ARGs for OS and 5 ARGs for DFS were constructed and showed that the survive time was significantly shorter in the high-risk group than in the low-risk group (P < 0.001). The ROC curve for OS exhibited good predictive accuracy, with an area under the curve value of 0.738. In the stratification analyses, the OS time of the high-risk group was shorter than that of the low-risk group stratified by different clinical variables. In conclusion, an autophagy-related signature for OS we constructed can independently predict the prognosis of ccRCC patient, and provide a deep understanding of the potential biological mechanisms of autophagy in ccRCC.
Project description:<h4>Background</h4>The prognostic nutritional index (PNI), an immunity and nutrition based prognostic score, was correlated with clinical outcomes in different tumors. However, the prognostic significance of PNI has not been investigated in hormone sensitive prostate cancer (PCa). The objective of this study was to determine the prognostic significance of PNI in hormone sensitive PCa.<h4>Methods</h4>Two hundred eighty PCa patients undergoing androgen deprivation therapy (ADT) as first line therapy at three centers were enrolled. The serum albumin levels and peripheral lymphocyte count were measured at the time of diagnosis. PNI was calculated as 10 * serum albumin (g/dL)?+?0.005 * total lymphocyte count (per mm3). Patients were categorized in two groups using a cut-off point of 50.2 as calculated by the receiver-operating curve analysis. Univariate and multivariate cox regression analyses were performed to evaluate PNI as a favorable prognostic factor for progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Prognostic accuracy was evaluated with the Harrell concordance index.<h4>Results</h4>Multivariate analyses identified PNI as an independent prognostic indicator with respect to PFS (hazard ratio (HR)?=?0.521, p =?0.001), CSS (HR?=?0.421, p =?0.002) and OS (HR?=?0.429, p =?0.001). Patients with elevated PNI had better clinical outcomes. The addition of PNI to the final models improved predictive accuracy (c-index: 0.758, 0.830 and 0.782) for PFS, CSS and OS compared with the clinicopathological base models (c-index: 0.736, 0.801 and 0.752), which included Gleason score and incidence of metastasis.<h4>Conclusions</h4>Elevated pretreatment PNI was a favorable prognostic indicator for PCa patients treated with ADT.
Project description:Background: Mucinous prostate cancer (PCa) is an extremely rare form of prostate malignancy. To date, the limited knowledge of its biology and outcomes stems from mostly small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results (SEER) database to explore the incidence and treatment of mucinous PCa together with its prognostic factors to gain relatively large and consolidated insights. Methods: Age-adjusted incidence (AAI) rates were evaluated over time. Propensity score matching (PSM) and Kaplan-Meier analyses were used to compare the prognosis between mucinous PCa and typical prostate acinar adenocarcinoma. We assessed cancer-specific survival (CSS) and overall survival (OS) after patient stratification according to summary stage and treatment choice. Cox hazards regression analysis was performed to determine independent predictors of CSS and OS. Results: The AAI in 2016 was 0.24 per million. Patients with mucinous PCa had similar CSS and OS to matched individuals with typical prostate acinar adenocarcinoma. In terms of treatment, 65.3% of mucinous PCa patients underwent surgery, and 23.9% received radiation therapy. Patients who underwent surgery had longer survival (CSS, p = 0.012; OS, p < 0.001), and patients who received radiation therapy had similar survival to those who did not receive radiation therapy (CSS, p = 0.794; OS, p = 0.097). A multivariate Cox analysis for CSS and OS showed that older age (CSS: HR: 4.982, p = 0.001; OS: HR: 4.258, p < 0.001) and distant stage (CSS: HR: 40.224, p < 0.001; OS: HR: 9.866, p < 0.001) were independent prognostic factors for mucinous PCa patients. Conclusions: Mucinous PCa has an extremely low AAI. Analysis of its outcomes indicates that it is not a more malignant tumor as previously suspected. Mucinous PCa shows a similar prognosis to typical prostate acinar carcinoma. Surgery was associated with prolonged survival. An older age at diagnosis and distant stage was associated with poor survival.
Project description:<h4>Background</h4>Several studies have demonstrated autophagy was involved in the process of esophageal adenocarcinoma (EAC). The aim of this study was to explore autophagy-related genes (ARGs) correlated with overall survival (OS) in EAC patients.<h4>Methods</h4>Expressions of ARGs in EAC and normal samples were downloaded from TCGA database. GO and KEGG enrichment analyses were used to investigate the ARGs bioinformatics functions. Univariate and multivariate cox regressions were performed to identify prognostic ARGs and the independent risk factors. ROC curve was established to evaluate the feasibility to predict the prognosis. Finally, the correlations between ARGs and clinical features were further explored. In addition, significantly different ARGs were verified in EAC specimens and normal esophageal mucosal tissues.<h4>Results</h4>Thirty significantly different ARGs were selected from EAC and normal tissues. Functional enrichments showed these ARGs were mainly related apoptosis. Multivariate cox regression analyses demonstrated eight ARGs were significantly associated with OS. Among these eight genes, BECN1 (HR?=?0.321, P =?0.046), DAPK1 (HR?=?0.636, P =?0.025) and CAPN1 (HR?=?0.395, P =?0.004) played protective roles in survival. Gender (HR?=?0.225, P =?0.032), stage (HR?=?5.841, P =?0.008) and risk score (HR?=?1.131, P < 0.001) were independent prognostic risk factors. ROC curves showed better efficacy to predict survival using the risk score. Additionally, we found BECN1, DAPK1, VAMP7 and SIRT1 genes were correlated significantly with survival status, gender, primary tumor and tumor stage (all P < 0.05). The experimental results confirmed the BIRC5 was overexpressed and the ITPR1, PRKN were downregulated in the EAC tissues compared with the normal esophageal mucosal tissues (all P < 0.05).<h4>Conclusion</h4>Our findings suggested that autophagy was involved in the process of EAC. Several ARGs probably could serve as diagnostic and prognostic biomarkers and may help facilitate therapeutic targets in EAC patients.
Project description:BACKGROUND:Bone is a preferential site for prostate cancer (PCa) metastasis. However, sites of synchronous distant metastases in PCa patients with bone metastases at initial diagnosis and their impacts on prognosis are still unclear, limiting our ability to better stratify and treat the patients. In this study, we examined the sites of synchronous extra-skeletal metastases in de novo PCa patients with bone metastases and their associated prognoses. METHODS:In total, 16,643 de novo PCa patients with bone metastases from the SEER database were included. After stratification of metastatic sites (bone, lung, liver, and brain) and treatment modalities, overall survival (OS) and independent predictors of OS, were analyzed. RESULTS:Lung was the most frequent site of synchronous metastases, followed by liver, while brain metastases were relatively uncommon. Patients with bone-only metastases showed the longest mean survival time (35.87 months, p?<?0.001), followed by patients with bone and lung metastases (30.74 months, p?<?0.001). Patients with bone and liver metastases had the shortest mean survival time (17.39 months, p?<?0.001). Age?>?70 years, unmarried status, high tumor grade, prostate-specific antigen (PSA)?>?50 ng/ml, and Gleason score???8 were associated with poor OS (all p?<?0.01). Asian or Pacific Islander ethnic background was associated with a favorable OS (all p?<?0.01). Chemotherapy improved OS in patients without brain metastases (all p?<?0.05). For patients with bone-only metastases, radical prostatectomy (RP) (HR, 0.339; 95% CI 0.231-0.495; p?<?0.001), brachytherapy (BT) (HR, 0.567; 95% CI 0.388-0.829; p?=?0.003), and chemotherapy (HR, 0.850; 95% CI 0.781-0.924; p?<?0.001) were associated with prolonged OS. CONCLUSIONS:Age, race, tumor grade, PSA, Gleason score, sites of synchronous extra-skeletal metastases, as well as treatment modalities affected OS in newly diagnosed PCa patients with bone metastases. Synchronous liver metastases were associated with poor OS. Chemotherapy improved OS in patients without brain metastases. RP and BT improved OS in patients with bone-only metastases. Further investigation is warranted to validate these findings.
Project description:The aim of this study was to focus on clinicopathological characteristics and prognosis in men with prostate cancer (PCa) harboring a breast cancer 2 (BRCA2) gene mutation and to offer convincing evidence to consider BRCA2 mutation as a marker of poor prognosis in the molecular classification of PCa. We searched relevant articles from PubMed, Embase, Web of Science, and the Cochrane Library databases to evaluate the differences in the overall survival (OS) and cancer-specific survival (CSS) between BRCA2 mutation carriers and non-carriers in patients with PCa. We included 525 BRCA2 mutation-carriers and 8,463 non-carriers in total from 10 studies in our meta-analysis. The results showed that carrying a BRCA2 mutation was correlated with a reduced CSS and OS when compared with that of non-carriers, with pooled Hazard Ratios (HRs) of 2.53 (95% confidence interval (CI): 2.10-3.06, P < 0.001) and 2.21 (95% CI: 1.64-2.99, P < 0.001), respectively. The results also demonstrated that BRCA2 mutation-carriers harbored a higher Gleason Score (GS) (> 7), TNM stage (> T3, N1, M1), and risk level than non-carriers. Our meta-analysis showed that a BRCA2 mutation predicted poor survival outcomes in patients with prostate cancer, especially in those undergoing treatments with radiotherapy. Therefore, the use of BRCA2 mutation as a clinical prognostic factor could help stratify the high-risk patients and provide clinical strategies for more effective targeted treatments for patients with prostate cancer.
Project description:Purpose: Autophagy is a major catabolic system by which eukaryotic cells undergo self-degradation of damaged, defective, or unwanted intracellular components. An abnormal autophagic level is implicated in the pathogenesis of multiple diseases, including cancers. The aim of this study is to explore the prognostic value of autophagy in bladder cancer (BC), which is a major cause of cancer-related death globally. Patients and methods: First, 27 differentially expressed autophagy-related genes (ARGs) were identified in BC patients based on The Cancer Genome Atlas (TCGA) database. Functional enrichment analyses hinted that autophagy may act in a tumor-suppressive role in the initiation of BC. Then, the Cox proportional hazard regression model were employed to identify three key prognostic ARGs (JUN, MYC, and ITGA3), which were related with overall survival (OS) significantly in BC. The three genes represented important clinical significance and prognostic value in BC. Then a prognostic index (PI) was constructed. Results: The PI was constructed based on the three genes, and significantly stratified BC patients into high- and low-risk groups in terms of OS (HR=1.610, 95% CI=1.200-2.160, P=0.002). PI remained as an independent prognostic factor in multivariate analyses (HR=2.355, 95% CI=1.483-3.739, P<0.001). When integrated with clinical characteristics of age and stage, an autophagy-clinical prognostic index (ACPI) was finally validated, which had improved performance in predicting OS of BC patients (HR=2.669, 95% CI=1.986-3.587, P<0.001). The ACPI was confirmed in datasets of GSE13507 (HR=7.389, 95% CI=3.645-14.980, P<0.001) and GSE31684 (HR=1.665, 95% CI=0.872-3.179, P=0.122). Conclusion: This study provides a potential prognostic signature for predicting prognosis of BC patients and molecular insights of autophagy in BC.
Project description:Autophagy, a major cause of cancer-related death, is correlated with the pathogenesis of various diseases including cancers. Our study aimed to develop an autophagy-related model for predicting prognosis of patients with laryngeal cancer.We analyzed the correlation between expression profiles of autophagy-related genes (ARGs) and clinical outcomes in 111 laryngeal cancer patients from The Cancer Genome Atlas (TCGA). Afterward, gene functional enrichment analyses of gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to find the major biological attributes. Univariate Cox regression analyses and multivariate Cox regression analyses were performed to screen ARGs whose expression profiles were significantly associated with laryngeal cancer patients overall survival (OS). Furthermore, to provide the doctors and patients with a quantitative method to perform an individualized survival prediction, we constructed a prognostic nomogram.Thirty eight differentially expressed ARGs were screened out in laryngeal cancer patients through the TCGA database. Related functional enrichments may act as tumor-suppressive roles in the tumorigenesis of laryngeal cancer. Subsequently, 4 key prognostic ARGs (IKBKB, ST13, TSC2, and MAP2K7) were identified from all ARGs by the Cox regression model, which significantly correlated with OS in laryngeal cancer. Furthermore, the risk score was constructed, which significantly divided laryngeal cancer patients into high- and low-risk groups. Integrated with clinical characteristics, gender, N and the risk score are very likely associated with patients OS. A prognostic nomogram of ARGs was constructed using the Cox regression model.Our study could provide a valuable prognostic model for predicting the prognosis of laryngeal cancer patients and a new understanding of autophagy in laryngeal cancer.