Cancer genomic, transcriptomic, and proteomic profiling has generated extensive data that necessitate the development of tools for its analysis and dissemination. We developed UALCAN to provide a portal for easy exploring, analyzing, and visualizing these data, allowing users to integrate the data to better understand the gene, proteins, and pathways perturbed in cancer and make discoveries. UALCAN web portal enables analyzing and delivering cancer transcriptome, proteomics, and patient survival data to the cancer research community. With data obtained from The Cancer Genome Atlas (TCGA) project, UALCAN has enabled users to evaluate protein-coding gene expression and its impact on patient survival across 33 types of cancers. The web portal has been used extensively since its release and received immense popularity, underlined by its usage from cancer researchers in more than 100 countries. The present manuscript highlights the task we have undertaken and updates that we have made to UALCAN since its release in 2017. Extensive user feedback motivated us to expand the resource by including data on a) microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and promoter DNA methylation from TCGA and b) mass spectrometry-based proteomics from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). UALCAN provides easy access to pre-computed, tumor subgroup-based gene/protein expression, promoter DNA methylation status, and Kaplan-Meier survival analyses. It also provides new visualization features to comprehend and integrate observations and aids in generating hypotheses for testing. UALCAN is accessible at http://ualcan.path.uab.edu

Mass-spectrometry-based proteomic profiling of human cancers has the potential for pan-cancer analyses to identify molecular subtypes and associated pathway features that might be otherwise missed using transcriptomics. Here, we classify 532 cancers, representing six tissue-based types (breast, colon, ovarian, renal, uterine), into ten proteome-based, pan-cancer subtypes that cut across tumor lineages. The proteome-based subtypes are observable in external cancer proteomic datasets surveyed. Gene signatures of oncogenic or metabolic pathways can further distinguish between the subtypes. Two distinct subtypes both involve the immune system, one associated with the adaptive immune response and T-cell activation, and the other associated with the humoral immune response. Two additional subtypes each involve the tumor stroma, one of these including the collagen VI interacting network. Three additional proteome-based subtypes—respectively involving proteins related to Golgi apparatus, hemoglobin complex, and endoplasmic reticulum—were not reflected in previous transcriptomics analyses. A data portal is available at UALCAN website.

Erlotinib (Tarceva) is an orally available HER1 (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of a range of human malignancies. In this study, we examine the capacity of erlotinib to modulate radiation response and investigate specific mechanisms underlying these interactions in human tumor cell lines and xenografts. The impact of erlotinib on cell cycle kinetics was analyzed using flow cytometry, and the impact on apoptosis was evaluated via fluorescein-labeled pan-caspase inhibition and poly(ADP-ribose) polymerase cleavage. Radiation-induced EGFR autophosphorylation and Rad51 expression were examined by Western blot analysis. Radiation survival was analyzed using a clonogenic assay and assessment of in vivo tumor growth was done using a mouse xenograft model system. Microarray studies were carried out using 20 K human cDNA microarray and select genes were validated using quantitative reverse transcription-PCR (RT-PCR). Independently, erlotinib and radiation induce accumulation of tumor cells in G 1 and G 2 -M phase, respectively, with a reduction of cells in S phase. When combined with radiation, erlotinib promotes a further reduction in S-phase fraction. Erlotinib enhances the induction of apoptosis, inhibits EGFR autophosphorylation and Rad51 expression following radiation exposure, and promotes an increase in radiosensitivity. Tumor xenograft studies confirm that systemic administration of erlotinib results in profound tumor growth inhibition when combined with radiation. cDNA microarray analysis assessing genes differentially regulated by erlotinib following radiation exposure identifies a diverse set of genes deriving from several functional classes. Validation is confirmed for several specific genes that may influence radiosensitization by erlotinib including Egr-1, CXCL1, and IL-1B. These results identify the capacity of erlotinib to enhance radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. Preliminary microarray data suggests additional mechanisms underlying the complex interaction between EGFR signaling and radiation response. These data suggest that the erlotinib/ radiation combination represents a strategy worthy of further examination in clinical trials. (Cancer Res 2005; 65(8): 3328-35)

Next-generation genomic sequencing has identified multiple novel molecular alterations in cancer. Since the identification of DNA methylation and histone modification, it has become evident that genes encoding epigenetic modifiers that locally and globally regulate gene expression play a crucial role in normal development and cancer progression. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the enzymatic catalytic subunit of the polycomb-repressive complex 2 (PRC2) that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). EZH2 is involved in global transcriptional repression, mainly targeting tumor-suppressor genes. EZH2 is commonly overexpressed in cancer and shows activating mutations in subtypes of lymphoma. Extensive studies have uncovered an important role for EZH2 in cancer progression and have suggested that it may be a useful therapeutic target. In addition, tumors harboring mutations in other epigenetic genes such as ARID1A, KDM6, and BAP1 are highly sensitive to EZH2 inhibition, thus increasing its potential as a therapeutic target. Recent studies also suggest that inhibition of EZH2 enhances the response to tumor immunotherapy. Many small-molecule inhibitors have been developed to target EZH2 or the PRC2 complex, with some of these inhibitors now in early clinical trials reporting clinical responses with acceptable tolerability. In this review, we highlight the recent advances in targeting EZH2, its successes, and potential limitations, and we discuss the future directions of this therapeutic subclass.

Global molecular profiling of cancers has shown broad utility in delineating pathways and processes underlying disease, in predicting prognosis and response to therapy, and in suggesting novel treatments. To gain further insights from such data, we have integrated and analyzed a comprehensive collection of "molecular concepts" representing > 2500 cancer-related gene expression signatures from Oncomine and manual curation of the literature, drug treatment signatures from the Connectivity Map, target gene sets from genome-scale regulatory motif analyses, and reference gene sets from several gene and protein annotation databases. We computed pairwise association analysis on all 13,364 molecular concepts and identified > 290,000 significant associations, generating hypotheses that link cancer types and subtypes, pathways, mechanisms, and drugs. To navigate a network of associations, we developed an analysis platform, the Molecular Concepts Map. We demonstrate the utility of the approach by highlighting molecular concepts analyses of Myc pathway activation, breast cancer relapse, and retinoic acid treatment.

Mass-spectrometry-based proteomic data on human tumors—combined with corresponding multi-omics data—present opportunities for systematic and pan-cancer proteogenomic analyses. Here, we assemble a compendium dataset of proteomics data of 2002 primary tumors from 14 cancer types and 17 studies. Protein expression of genes broadly correlates with corresponding mRNA levels or copy number alterations (CNAs) across tumors, but with notable exceptions. Based on unsupervised clustering, tumors separate into 11 distinct proteome-based subtypes spanning multiple tissue-based cancer types. Two subtypes are enriched for brain tumors, one subtype associating with MYC, Wnt, and Hippo pathways and high CNA burden, and another subtype associating with metabolic pathways and low CNA burden. Somatic alteration of genes in a pathway associates with higher pathway activity as inferred by proteome or transcriptome data. A substantial fraction of cancers shows high MYC pathway activity without MYC copy gain but with mutations in genes with noncanonical roles in MYC. Our proteogenomics survey reveals the interplay between genome and proteome across tumor lineages.

Ischemic cardiomyopathy (ICM) is the clinical endpoint of coronary heart disease and a leading cause of heart failure. Despite growing demands to develop personalized approaches to treat ICM, progress is limited by inadequate knowledge of its pathogenesis. Since epigenetics has been implicated in the development of other chronic diseases, the current study was designed to determine whether transcriptional and/or epigenetic changes are sufficient to distinguish ICM from other etiologies of heart failure. Specifically, we hypothesize that genome-wide DNA methylation encodes transcriptional reprogramming in ICM. RNA-sequencing analysis was performed on human ischemic left ventricular tissue obtained from patients with end-stage heart failure, which enriched known targets of the polycomb methyltransferase EZH2 compared to non-ischemic hearts. Combined RNA sequencing and genome-wide DNA methylation analysis revealed a robust gene expression pattern consistent with suppression of oxidative metabolism, induced anaerobic glycolysis, and altered cellular remodeling. Lastly, KLF15 was identified as a putative upstream regulator of metabolic gene expression that was itself regulated by EZH2 in a SET domain-dependent manner. Our observations therefore define a novel role of DNA methylation in the metabolic reprogramming of ICM. Furthermore, we identify EZH2 as an epigenetic regulator of KLF15 along with DNA hypermethylation, and we propose a novel mechanism through which coronary heart disease reprograms the expression of both intermediate enzymes and upstream regulators of cardiac metabolism such as KLF15.

Ovarian cancer is the fifth leading cause of cancer-related deaths in females in the United States. There were an estimated 22,440 new cases and 14,080 deaths due to ovarian cancer in 2017. Most patients present with advanced-stage disease, revealing the urgent need for new therapeutic strategies targeting pathways of tumorigenesis and chemotherapy resistance. While multiple genomic changes contribute to the progression of this aggressive disease, it has become increasingly evident that epigenetic events play a pivotal role in ovarian cancer development. One of the well-studied epigenetic modifiers, the histone methyltransferase EZH2, is a member of polycomb repressive complex 2 (PRC2) and is commonly involved in transcriptional repression. EZH2 is the enzymatic catalytic subunit of the PRC2 complex that can alter gene expression by trimethylating lysine 27 on histone 3 (H3K27). In ovarian cancer, EZH2 is commonly overexpressed and therefore potentially serves as an effective therapeutic target. Multiple small-molecule inhibitors are being developed to target EZH2, which are now in clinical trials. Thus, in this review, we highlight the progress made in EZH2-related research in ovarian cancer and discuss the potential utility of targeting EZH2 with available small-molecule inhibitors for ovarian cancer. .