Integrated Analysis of Transcriptomic and Genomic Data Reveals Blood Biomarkers With Diagnostic and Prognostic Potential in Non-small Cell Lung Cancer.

Background: Lung cancer is the second most common cancer and the main leading cause of cancer-associated death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer diagnoses and more than 50% of all lung cancer cases are diagnosed at an advanced stage; hence have poor prognosis. Therefore, it is important to diagnose NSCLC patients reliably and as early as possible in order to reduce the risk of mortality. Methods: We identified blood-based gene markers for early NSCLC by performing a multi-omics approach utilizing integrated analysis of global gene expression and copy number alterations of NSCLC patients using array-based techniques. We also validated the diagnostic and the prognostic potential of the gene signature using independent datasets with detailed clinical information. Results: We identified 12 genes that are significantly expressed in NSCLC patients' blood, at the earliest stages of the disease, and associated with a poor disease outcome. We then validated 12-gene signature's diagnostic and prognostic value using independent datasets of gene expression profiling of over 1000 NSCLC patients. Indeed, 12-gene signature predicted disease outcome independently of other clinical factors in multivariate regression analysis (HR = 2.64, 95% CI = 1.72-4.07; p = 1.3 × 10-8). Significantly altered functions, pathways, and gene networks revealed alterations in several key genes and cancer-related pathways that may have importance for NSCLC transformation, including FAM83A, ZNF696, UBE2C, RECK, TIMM50, GEMIN7, and XPO5. Conclusion: Our findings suggest that integrated genomic and network analyses may provide a reliable approach to identify genes that are associated with NSCLC, and lead to improved diagnosis detecting the disease in early stages in patients' blood instead of using invasive techniques and also have prognostic potential for discriminating high-risk patients from the low-risk ones.

Transcriptomic data analysis coupled with copy number aberrations reveals a blood-based 17-gene signature for diagnosis and prognosis of patients with colorectal cancer.

Background: Colorectal cancer (CRC) is the third most common cancer and third leading cause of cancer-associated deaths worldwide. Diagnosing CRC patients reliably at an early and curable stage is of utmost importance to reduce the risk of mortality. Methods: We identified global differentially expressed genes with copy number alterations in patients with CRC. We then identified genes that are also expressed in blood, which resulted in a blood-based gene signature. We validated the gene signature's diagnostic and prognostic potential using independent datasets of gene expression profiling from over 800 CRC patients with detailed clinical data. Functional enrichment, gene interaction networks and pathway analyses were also performed. Results: The analysis revealed a 17-gene signature that is expressed in blood and demonstrated that it has diagnostic potential. The 17-gene SVM classifier displayed 99 percent accuracy in predicting the patients with CRC. Moreover, we developed a prognostic model and defined a risk-score using 17-gene and validated that high risk score is strongly associated with poor disease outcome. The 17-gene signature predicted disease outcome independent of other clinical factors in the multivariate analysis (HR = 2.7, 95% CI = 1.3-5.3, p = 0.005). In addition, our gene network and pathway analyses revealed alterations in oxidative stress, STAT3, ERK/MAPK, interleukin and cytokine signaling pathways as well as potentially important hub genes, including BCL2, MS4A1, SLC7A11, AURKA, IL6R, TP53, NUPR1, DICER1, DUSP5, SMAD3, and CCND1. Conclusion: Our results revealed alterations in various genes and cancer-related pathways that may be essential for CRC transformation. Moreover, our study highlights diagnostic and prognostic value of our gene signature as well as its potential use as a blood biomarker as a non-invasive diagnostic method. Integrated analysis transcriptomic data coupled with copy number aberrations may provide a reliable method to identify key biological programs associated with CRC and lead to improved diagnosis and therapeutic options.

A Network-Based Methodology to Identify Subnetwork Markers for Diagnosis and Prognosis of Colorectal Cancer.

The development of reliable methods for identification of robust biomarkers for complex diseases is critical for disease diagnosis and prognosis efforts. Integrating multi-omics data with protein-protein interaction (PPI) networks to investigate diseases may help better understand disease characteristics at the molecular level. In this study, we developed and tested a novel network-based method to detect subnetwork markers for patients with colorectal cancer (CRC). We performed an integrated omics analysis using whole-genome gene expression profiling and copy number alterations (CNAs) datasets followed by building a gene interaction network for the significantly altered genes. We then clustered the constructed gene network into subnetworks and assigned a score for each significant subnetwork. We developed a support vector machine (SVM) classifier using these scores as feature values and tested the methodology in independent CRC transcriptomic datasets. The network analysis resulted in 15 subnetwork markers that revealed several hub genes that may play a significant role in colorectal cancer, including PTP4A3, FGFR2, PTX3, AURKA, FEN1, INHBA, and YES1. The 15-subnetwork classifier displayed over 98 percent accuracy in detecting patients with CRC. In comparison to individual gene biomarkers, subnetwork markers based on integrated multi-omics and network analyses may lead to better disease classification, diagnosis, and prognosis.

Identification of Gene Signature as Diagnostic and Prognostic Blood Biomarker for Early Hepatocellular Carcinoma Using Integrated Cross-Species Transcriptomic and Network Analyses.

Background: Hepatocellular carcinoma (HCC) is considered the most common type of liver cancer and the fourth leading cause of cancer-related deaths in the world. Since the disease is usually diagnosed at advanced stages, it has poor prognosis. Therefore, reliable biomarkers are urgently needed for early diagnosis and prognostic assessment. Methods: We used genome-wide gene expression profiling datasets from human and rat early HCC (eHCC) samples to perform integrated genomic and network-based analyses, and discovered gene markers that are expressed in blood and conserved in both species. We then used independent gene expression profiling datasets for peripheral blood mononuclear cells (PBMCs) for eHCC patients and from The Cancer Genome Atlas (TCGA) database to estimate the diagnostic and prognostic performance of the identified gene signature. Furthermore, we performed functional enrichment, interaction networks and pathway analyses. Results: We identified 41 significant genes that are expressed in blood and conserved across species in eHCC. We used comprehensive clinical data from over 600 patients with HCC to verify the diagnostic and prognostic value of 41-gene-signature. We developed a prognostic model and a risk score using the 41-geneset that showed that a high prognostic index is linked to a worse disease outcome. Furthermore, our 41-gene signature predicted disease outcome independently of other clinical factors in multivariate regression analysis. Our data reveals a number of cancer-related pathways and hub genes, including EIF4E, H2AFX, CREB1, GSK3B, TGFBR1, and CCNA2, that may be essential for eHCC progression and confirm our gene signature's ability to detect the disease in its early stages in patients' biological fluids instead of invasive procedures and its prognostic potential. Conclusion: Our findings indicate that integrated cross-species genomic and network analysis may provide reliable markers that are associated with eHCC that may lead to better diagnosis, prognosis, and treatment options.