Genetic co-expression networks contribute to creating predictive model and exploring novel biomarkers for the prognosis of breast cancer.

Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10-8) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.

Six novel immunoglobulin genes as biomarkers for better prognosis in triple-negative breast cancer by gene co-expression network analysis.

Gene co-expression network analysis (GCNA) can detect alterations in regulatory activities in case/control comparisons. We propose a framework to detect novel genes and networks for predicting breast cancer recurrence. Thirty-four prognosis candidate genes were selected based on a literature review. Four Gene Expression Omnibus Series (GSE) microarray datasets (n = 920) were used to create gene co-expression networks based on these candidates. We applied the framework to four comparison groups according to node (+/-) and recurrence (+/-). We identified a sub-network containing two candidate genes (LST1 and IGHM) and six novel genes (IGHA1, IGHD, IGHG1, IGHG3, IGLC2, and IGLJ3) related to B cell-specific immunoglobulin. These novel genes were correlated with recurrence under the control of node status and were found to function as tumor suppressors; higher mRNA expression indicated a lower risk of recurrence (hazard ratio, HR = 0.87, p = 0.001). We created an immune index score by performing principle component analysis and divided the genes into low and high groups. This discrete index significantly predicted relapse-free survival (RFS) (high: HR = 0.77, p = 0.019; low: control). Public tool KM Plotter and TCGA-BRCA gene expression data were used to validate. We confirmed these genes are correlated with RFS and distal metastasis-free survival (DMFS) in triple-negative breast cancer (TNBC) and general breast cancer.

Risk analysis of colorectal cancer incidence by gene expression analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the leading cancers worldwide. Several studies have performed microarray data analyses for cancer classification and prognostic analyses. Microarray assays also enable the identification of gene signatures for molecular characterization and treatment prediction. OBJECTIVE: Microarray gene expression data from the online Gene Expression Omnibus (GEO) database were used to to distinguish colorectal cancer from normal colon tissue samples. METHODS: We collected microarray data from the GEO database to establish colorectal cancer microarray gene expression datasets for a combined analysis. Using the Prediction Analysis for Microarrays (PAM) method and the GSEA MSigDB resource, we analyzed the 14,698 genes that were identified through an examination of their expression values between normal and tumor tissues. RESULTS: Ten genes (ABCG2, AQP8, SPIB, CA7, CLDN8, SCNN1B, SLC30A10, CD177, PADI2, and TGFBI) were found to be good indicators of the candidate genes that correlate with CRC. From these selected genes, an average of six significant genes were obtained using the PAM method, with an accuracy rate of 95%. The results demonstrate the potential of utilizing a model with the PAM method for data mining. After a detailed review of the published reports, the results confirmed that the screened candidate genes are good indicators for cancer risk analysis using the PAM method. CONCLUSIONS: Six genes were selected with 95% accuracy to effectively classify normal and colorectal cancer tissues. We hope that these results will provide the basis for new research projects in clinical practice that aim to rapidly assess colorectal cancer risk using microarray gene expression analysis.

Gene expression profile of peripheral blood in colorectal cancer.

AIM: Optimal molecular markers for detecting colorectal cancer (CRC) in a blood-based assay were evaluated. METHODS: A matched (by variables of age and sex) case-control design (111 CRC and 227 non-cancer samples) was applied. Total RNAs isolated from the 338 blood samples were reverse-transcribed, and the relative transcript levels of candidate genes were analyzed. The training set was made of 162 random samples of the total 338 samples. A logistic regression analysis was performed, and odds ratios for each gene were determined between CRC and non-cancer. The samples (n = 176) in the testing set were used to validate the logistic model, and an inferred performance (generality) was verified. By pooling 12 public microarray datasets(GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105), which included 519 cases of adenocarcinoma and 88 controls of normal mucosa, we were able to verify the selected genes from logistic models and estimate their external generality. RESULTS: The logistic regression analysis resulted in the selection of five significant genes (P < 0.05; MDM2, DUSP6, CPEB4, MMD, and EIF2S3), with odds ratios of 2.978, 6.029, 3.776, 0.538 and 0.138, respectively. The five-gene model performed stably for the discrimination of CRC cases from controls in the training set, with accuracies ranging from 73.9% to 87.0%, a sensitivity of 95% and a specificity of 95%. In addition, a good performance in the test set was obtained using the discrimination model, providing 83.5% accuracy, 66.0% sensitivity, 92.0% specificity, a positive predictive value of 89.2% and a negative predictive value of 73.0%. Multivariate logistic regressions analyzed 12 pooled public microarray data sets as an external validation. Models that provided similar expected and observed event rates in subgroups were termed well calibrated. A model in which MDM2, DUSP6, CPEB4, MMD, and EIF2S3 were selected showed the result in logistic regression analysis (H-L P = 0.460, R2= 0.853, AUC = 0.978, accuracy = 0.949, specificity = 0.818 and sensitivity = 0.971). CONCLUSION: A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.