scholarly journals A Transcription Factor-Based Risk Model for Predicting the Prognosis of Prostate Cancer and Potential Therapeutic Drugs

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Ruixiang Luo ◽  
Mengjun Huang ◽  
Yinhuai Wang

Background. Prostate cancer (PC) is one of the most critical cancers affecting men’s health worldwide. The development of many cancers involves dysregulation or mutations in key transcription factors. This study established a transcription factor-based risk model to predict the prognosis of PC and potential therapeutic drugs. Materials and Methods. In this study, RNA-sequencing data were downloaded and analyzed using The Cancer Genome Atlas dataset. A total of 145 genes related to the overall survival rate of PC patients were screened using the univariate Cox analysis. The Kdmist clustering method was used to classify prostate adenocarcinoma (PRAD), thereby determining the cluster related to the transcription factors. The support vector machine-recursive feature elimination method was used to identify genes related to the types of transcription factors and the key genes specifically upregulated or downregulated were screened. These genes were further analyzed using Lasso to establish a model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for the functional analysis. The TIMER algorithm was used to quantify the abundance of immune cells in PRAD samples. The chemotherapy response of each GBM patient was predicted based on the public pharmacogenomic database, Genomics of Drug Sensitivity in Cancer (GDSC, http://www.cancerrxgene.org). The R package “pRRophetic” was applied to drug sensitivity (IC50) value prediction. Results. We screened 10 genes related to prognosis, including eight low-risk genes and two high-risk genes. The receiver operating characteristic (ROC) curve was 0.946. Patients in the high-risk score group had a poorer prognosis than those in the low-risk score group. The average area under the curve value of the model at different times was higher than 0.8. The risk score was an independent prognostic factor. Compared with the low-risk score group, early growth response-1 (EGR1), CACNA2D1, AC005831.1, SLC52A3, TMEM79, IL20RA, CRACR2A, and FAM189A2 expressions in the high-risk score group were decreased, while AC012181.1 and TRAPPC8 expressions were increased. GO and KEGG analyses showed that prognosis was related to various cancer signaling pathways. The proportion of B_cell, T_cell_CD4, and macrophages in the high-risk score group was significantly higher than that in the low-risk score group. A total of 25 classic immune checkpoint genes were screened out to express abnormally high-risk scores, and there were significant differences. Thirty mutant genes were identified; in the high- and low-risk score groups, SPOP, TP53, and TTN had the highest mutation frequency, and their mutations were mainly missense mutations. A total of 36 potential drug candidates for the treatment of PC were screened and identified. Conclusions. Ten genes of both high-and low-risk scores were associated with the prognosis of PC. PC prognosis may be related to immune disorders. SPOP, TP53, and TTN may be potential targets for the prognosis of PC.

2021 ◽  
Vol 12 ◽  
Author(s):  
JingJing Zhang ◽  
Pengcheng He ◽  
Xiaoning Wang ◽  
Suhua Wei ◽  
Le Ma ◽  
...  

Background: RNA-binding proteins (RBPs) act as important regulators in the progression of tumors. However, their role in the tumorigenesis and prognostic assessment in multiple myeloma (MM), a B-cell hematological cancer, remains elusive. Thus, the current study was designed to explore a novel prognostic B-cell-specific RBP signature and the underlying molecular mechanisms.Methods: Data used in the current study were obtained from the Gene Expression Omnibus (GEO) database. Significantly upregulated RBPs in B cells were defined as B cell-specific RBPs. The biological functions of B-cell-specific RBPs were analyzed by the cluster Profiler package. Univariate and multivariate regressions were performed to identify robust prognostic B-cell specific RBP signatures, followed by the construction of the risk classification model. Gene set enrichment analysis (GSEA)-identified pathways were enriched in stratified groups. The microenvironment of the low- and high-risk groups was analyzed by single-sample GSEA (ssGSEA). Moreover, the correlations among the risk score and differentially expressed immune checkpoints or differentially distributed immune cells were calculated. The drug sensitivity of the low- and high-risk groups was assessed via Genomics of Drug Sensitivity in Cancer by the pRRophetic algorithm. In addition, we utilized a GEO dataset involving patients with MM receiving bortezomib therapy to estimate the treatment response between different groups.Results: A total of 56 B-cell-specific RBPs were identified, which were mainly enriched in ribonucleoprotein complex biogenesis and the ribosome pathway. ADAR, FASTKD1 and SNRPD3 were identified as prognostic B-cell specific RBP signatures in MM. The risk model was constructed based on ADAR, FASTKD1 and SNRPD3. Receiver operating characteristic (ROC) curves revealed the good predictive capacity of the risk model. A nomogram based on the risk score and other independent prognostic factors exhibited excellent performance in predicting the overall survival of MM patients. GSEA showed enrichment of the Notch signaling pathway and mRNA cis-splicing via spliceosomes in the high-risk group. Moreover, we found that the infiltration of diverse immune cell subtypes and the expression of CD274, CD276, CTLA4 and VTCN1 were significantly different between the two groups. In addition, the IC50 values of 11 drugs were higher in the low-risk group. Patients in the low-risk group exhibited a higher complete response rate to bortezomib therapy.Conclusion: Our study identified novel prognostic B-cell-specific RBP biomarkers in MM and constructed a unique risk model for predicting MM outcomes. Moreover, we explored the immune-related mechanisms of B cell-specific RBPs in regulating MM. Our findings could pave the way for developing novel therapeutic strategies to improve the prognosis of MM patients.


2021 ◽  
Vol 11 ◽  
Author(s):  
Jian-yu Shi ◽  
Yan-yan Bi ◽  
Bian-fang Yu ◽  
Qing-feng Wang ◽  
Dan Teng ◽  
...  

Despite extensive research, the exact mechanisms involved in colorectal cancer (CRC) etiology and pathogenesis remain unclear. This study aimed to examine the correlation between tumor-associated alternative splicing (AS) events and tumor immune infiltration (TII) in CRC. We analyzed transcriptome profiling and clinical CRC data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq and Innate databases, respectively to develop and validate a risk model of differential AS events and subsequently a TII risk model. We then conducted a two-factor survival analysis to study the association between TII and AS risk and evaluated the associations between immune signatures and six types of immune cells based on the TIMER database. Subsequently, we studied the distribution of six types of TII cells in high- and low-risk groups for seven AS events and in total. We obtained the profiles of AS events/genes for 484 patients, which included 473 CRC tumor samples and 41 corresponding normal samples, and detected 22581 AS events in 8122 genes. Exon Skip (ES) (8446) and Mutually Exclusive Exons (ME) (74) exhibited the most and fewest AS events, respectively. We then classified the 433 patients with CRC into low-risk (n = 217) and high-risk (n = 216) groups based on the median risk score in different AS events. Compared with patients with low-risk scores (mortality = 11.8%), patients with high-risk scores were associated with poor overall survival (mortality = 27.6%). The risk score, cancer stage, and pathological stage (T, M, and N) were closely correlated with prognosis in patients with CRC (P < 0.001). We identified 6479 differentially expressed genes from the transcriptome profiles of CRC and intersected 468 differential immune-related signatures. High-AS-risk and high-TII-risk predicted a poor prognosis in CRC. Different AS types were associated with different TII risk characteristics. Alternate Acceptor site (AA) and Alternate Promoter (AP) events directly affected the concentration of CD4T cells, and the level of CD8T cells was closely correlated with Alternate Terminator (AT) and Exon Skip (ES) events. Thus, the concentration of CD4T and CD8T cells in the CRC immune microenvironment was not specifically modulated by AS. However, B cell, dendritic cell, macrophage, and neutrophilic cell levels were strongly correlated with AS events. These results indicate adverse associations between AS event risk levels and immune cell infiltration density. Taken together, our findings show a clear association between tumor-associated alternative splicing and immune cell infiltration events and patient outcome and could form a basis for the identification of novel markers and therapeutic targets for CRC and other cancers in the future.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Carly A. Conran ◽  
Zhuqing Shi ◽  
William Kyle Resurreccion ◽  
Rong Na ◽  
Brian T. Helfand ◽  
...  

Abstract Background Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention. Methods This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40–70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups. Results The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants’ reported optimism about their future health neither before nor after receiving GRS results. Conclusions Genetic risk scores that quantify an individual’s risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ganna Leonenko ◽  
Emily Baker ◽  
Joshua Stevenson-Hoare ◽  
Annerieke Sierksma ◽  
Mark Fiers ◽  
...  

AbstractPolygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region) with pT<0.1 for SNP selection. Prediction accuracy in a sample across different PRS approaches is similar, but individuals’ scores and their associated ranking differ. We show that standardising PRS against the population mean, as opposed to the sample mean, makes the individuals’ scores comparable between studies. Our work highlights the best strategies for polygenic profiling when assessing individuals for AD risk.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tuo Liang ◽  
Jiarui Chen ◽  
GuoYong Xu ◽  
Zide Zhang ◽  
Jiang Xue ◽  
...  

AbstractWe established a relationship among the immune-related genes, tumor-infiltrating immune cells (TIICs), and immune checkpoints in patients with osteosarcoma. The gene expression data for osteosarcoma were downloaded from UCSC Xena and GEO database. Immune-related differentially expressed genes (DEGs) were detected to calculate the risk score. “Estimate” was used for immune infiltrating estimation and “xCell” was used to obtain 64 immune cell subtypes. Furthermore, the relationship among the risk scores, immune cell subtypes, and immune checkpoints was evaluated. The three immune-related genes (TYROBP, TLR4, and ITGAM) were selected to establish a risk scoring system based on their integrated prognostic relevance. The GSEA results for the Hallmark and KEGG pathways revealed that the low-risk score group exhibited the most gene sets that were related to immune-related pathways. The risk score significantly correlated with the xCell score of macrophages, M1 macrophages, and M2 macrophages, which significantly affected the prognosis of osteosarcoma. Thus, patients with low-risk scores showed better results with the immune checkpoints inhibitor therapy. A three immune-related, gene-based risk model can regulate macrophage activation and predict the treatment outcomes the survival rate in osteosarcoma.


2020 ◽  
Author(s):  
Bin Wu ◽  
Yi Yao ◽  
Yi Dong ◽  
Si Qi Yang ◽  
Deng Jing Zhou ◽  
...  

Abstract Background:We aimed to investigate an immune-related long non-coding RNA (lncRNA) signature that may be exploited as a potential immunotherapy target in colon cancer. Materials and methods: Colon cancer samples from The Cancer Genome Atlas (TCGA) containing available clinical information and complete genomic mRNA expression data were used in our study. We then constructed immune-related lncRNA co-expression networks to identify the most promising immune-related lncRNAs. According to the risk score developed from screened immune-related lncRNAs, the high-risk and low-risk groups were separated on the basis of the median risk score, which served as the cutoff value. An overall survival analysis was then performed to confirm that the risk score developed from screened immune-related lncRNAs could predict colon cancer prognosis. The prediction reliability was further evaluated in the independent prognostic analysis and receiver operating characteristic curve (ROC). A principal component analysis (PCA) and gene set enrichment analysis (GSEA) were performed for functional annotation. Results: Information for a total of 514 patients was included in our study. After multiplex analysis, 12 immune-related lncRNAs were confirmed as a signature to evaluate the risk scores for each patient with cancer. Patients in the low-risk group exhibited a longer overall survival (OS) than those in the high-risk group. Additionally, the risk scores were an independent factor, and the Area Under Curve (AUC) of ROC for accuracy prediction was 0.726. Moreover, the low-risk and high-risk groups displayed different immune statuses based on principal components and gene set enrichment analysis.Conclusions: Our study suggested that the signature consisting of 12 immune-related lncRNAs can provide an accessible approach to measuring the prognosis of colon cancer and may serve as a valuable antitumor immunotherapy.


2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Hui Xiong ◽  
Hui Gao ◽  
Jinding Hu ◽  
Yun Dai ◽  
Hanbo Wang ◽  
...  

Compelling evidence indicates that immune function is correlated with the prognosis of bladder cancer (BC). Here, we aimed to develop a clinically translatable immune-related gene pairs (IRGPs) prognostic signature to estimate the overall survival (OS) of bladder cancer. From the 251 prognostic-related IRGPs, 37 prognostic-related IRGPs were identified using LASSO regression. We identified IRGPs with the potential to be prognostic markers. The established risk scores divided BC patients into high and low risk score groups, and the survival analysis showed that risk score was related to OS in the TCGA-training set ( p < 0.001 ; HR = 7.5 [5.3, 10]). ROC curve analysis showed that the AUC for the 1-year, 3-year, and 5-year follow-up was 0.820, 0.883, and 0.879, respectively. The model was verified in the TCGA-testing set and external dataset GSE13507. Multivariate analysis showed that risk score was an independent prognostic predictor in patients with BC. In addition, significant differences were found in gene mutations, copy number variations, and gene expression levels in patients with BC between the high and low risk score groups. Gene set enrichment analysis showed that, in the high-risk score group, multiple immune-related pathways were inhibited, and multiple mesenchymal phenotype-related pathways were activated. Immune infiltration analysis revealed that immune cells associated with poor prognosis of BC were upregulated in the high-risk score group, whereas immune cells associated with a better prognosis of BC were downregulated in the high-risk score group. Other immunoregulatory genes were also differentially expressed between high and low risk score groups. A 37 IRGPs-based risk score signature is presented in this study. This signature can efficiently classify BC patients into high and low risk score groups. This signature can be exploited to select high-risk BC patients for more targeted treatment.


2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 72-72
Author(s):  
John L. Gore ◽  
Darlene Dai ◽  
Robert Benjamin Den ◽  
Kasra Yousefi ◽  
Tiffany Le ◽  
...  

72 Background: Prostate cancer patients and providers confront uncertainty as they consider adjuvant or salvage radiation therapy (ART, SRT) after radical prostatectomy (RP). We prospectively evaluated the impact of the Decipher RP test, which predicts metastasis risk after RP, on decision-making for postoperative radiation therapy. Methods: Between October 2016 and May 2017, 1,319 patients treated with RP and considering ART or SRT were enrolled into a Medicare Certification and Training Registry (CTR). Providers submitted a management recommendation based on initial clinical and pathology findings prior to obtaining the Decipher RP test and again upon receiving test results. Only Medicare patients that met the Local Coverage Determination inclusion criteria (i.e., non-organ confined prostate cancer or positive margins or rising PSA) and whose provider was certified in the CTR registry were included in the analysis. Results: Based on clinical variables alone, treatment was recommended for 26% of adjuvant and 19% of salvage patients. Obtaining a Decipher score, changed treatment recommendations in 34% (95% CI 30-39%) and 28% (95% CI 19-38%) of men considering adjuvant or salvage therapy respectively. Among men considering ART, 9% of Decipher low risk patients and 45% of Decipher high-risk patients were recommended treatment. Multivariable logistic regression demonstrated that – independent of pathology risk factors, a high-risk Decipher score was associated with an odds ratio of 7.3 (95% CI 3.9-14.2 p < 0.001) in the adjuvant and 5.5 (95% CI, 1.3-27.8, p = 0.026) in the salvage setting. Conclusions: A prospective CTR demonstrated that use of Decipher resulted in significant changes in treatment decisions for Medicare beneficiaries with PCa considering adjuvant and salvage therapies. Ongoing prospective studies aim at determining how increased use of therapy in men with high Decipher risk impacts oncologic outcomes and whether decreased use in Decipher low risk individuals improves health related quality of life without harming patient survival.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7016-7016
Author(s):  
Piyanuch Kongtim ◽  
Omar Hasan ◽  
Jorge Miguel Ramos Perez ◽  
Ankur Varma ◽  
Julianne Chen ◽  
...  

7016 Background: Molecular data and minimal residual disease (MRD) have been shown to influence outcomes in AML patients undergoing allogeneic hematopoietic cell transplantation (AHCT). Here we developed and validated a novel AML-specific Disease Risk Group (AML-DRG) and revise our previously developed Hematopoietic Cell Transplant - Composite Risk (HCT-CR) model by incorporating molecular data and MRD status before transplant to predict post-transplant outcomes of patients with AML. Methods: The study included 1414 consecutively treated adult AML patients, who received first AHCT between 1/2005-8/2018 at our institution. Patients were randomly assigned into a training (N = 944) and validation set (N = 470). To develop the AML-DRG model, the coefficient of all significant AML-related variables in multivariable Cox’s regression analysis (MVA) in a training dataset was converted into scores.The AML-DRG was the sum of scores from all significant covariates, while the AML-HCT-CR was the sum of disease-related factors assessed by the AML-DRG model with the addition of weighted scores from patient-related factors. Results: Based on results of MVA, the following scores were assigned to each AML-related variable; 1 point to secondary AML; 1 point to the 2017 ELN adverse risk; 2 points to CR with MRD positive/unknown; and 4 points to active disease at transplant. These were used to generate the AML-DRG (low-risk score 0-2; intermediate-risk score 3-4; and high-risk score > 4) with significantly different OS with HR of 2.02 (P < 0.001), and 3.85 (P < 0.001) for intermediate and high risk group compared with low risk group. By adding 1 point for patients > / = 60 years or HCT-CI > 3 to the AML-DRG, we created 4 risk groups of AML-HCT-CR (low-risk: score 0-2; intermediate-risk: score 3; high-risk: score 4 and very high-risk: score ≥5) with distinct survival outcomes. The AML-DRG and AML-HCT-CR model had C-index of 0.672 and 0.715, respectively which were better compared with DRI, ELN2017 and cytogenetic risk model. Conclusions: Prognostic models incorporating molecular data and MRD status before transplant allow better stratification and improved survival estimates of AML patients post-transplant.


Author(s):  
JinQun Jiang ◽  
HongYan Xu ◽  
PingShen Zhao ◽  
Hai Lu

Cervical cancer is a common malignancy in women and has a poor prognosis.More and more studies have shown that autophagy disorder is closely related to the occurrence of tumors. However, the prognostic role of autophagy gene in cervical cancer is still unclear. In this study, we constructed the risk signatures of autophagy related genes to predict the prognosis of cervical cancer. The expression profiles and clinical information of autophagy gene sets were downloaded from the TCGA and GES52903 queues as training sets and validation sets. The cervical normal tissue expression profile data from UCSC XENA website is GTEx data as a supplement to TCGA normal cervical tissue. Univariate COX regression analysis of 17 different autophagy genes with the Consensus approach tumor samples from the TCGA is divided into six subtypes, and the clinical traits in the six subtypes have different distribution, with further then absolute shrinkage and selection operator (LASSO) and multiariable COX regression method finally got seven autophagy genetic risk model is constructed, in the training set, the survival rate of high risk group is lower than the low risk group (p &lt; 0.0001), the validation set,The AUC area of the receiver operating characteristic (ROC) curve, the training set is 0.894, and the verification set is 0.736. We find that the high and low risk score is closely related to the TMN stage (All P is less than 0.05).The nomogram shows that the risk score combined with other indicators such as age, G,T,M, and N better predicts 1-year, 2-year, 3-year survival, and the DCA curve shows that the risk model combined with other indicators produces better clinical efficacy.Then immune cells in 28 in the enrichment score, there were statistically significant differences, high and low risk most GSEA enrichment analysis, the main enrichment in G2 / M checkpoint high-risk score, Genes defining epithelial and mesenchymal transition, raised in response to the low oxygen levels (hypoxia) gene, gene is important to the mitotic spindle assembly, these are closely related with the occurrence of tumor . In conclusion, our constructed autophagy risk signature may be a prognostic tool for cervical cancer.


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