Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

The Immune Landscape of Cancer

We performed an extensive immunogenomic anal-ysis of more than 10,000 tumors comprising 33diverse cancer types by utilizing data compiled byTCGA. Across cancer types, we identified six im-mune subtypes\u2014wound healing, IFN-gdominant,inflammatory, lymphocyte depleted, immunologi-cally quiet, and TGF-bdominant\u2014characterized bydifferences in macrophage or lymphocyte signa-tures, Th1:Th2 cell ratio, extent of intratumoral het-erogeneity, aneuploidy, extent of neoantigen load,overall cell proliferation, expression of immunomod-ulatory genes, and prognosis. Specific drivermutations correlated with lower (CTNNB1,NRAS,orIDH1) or higher (BRAF,TP53,orCASP8) leukocytelevels across all cancers. Multiple control modalitiesof the intracellular and extracellular networks (tran-scription, microRNAs, copy number, and epigeneticprocesses) were involved in tumor-immune cell inter-actions, both across and within immune subtypes.Our immunogenomics pipeline to characterize theseheterogeneous tumors and the resulting data areintended to serve as a resource for future targetedstudies to further advance the field

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility

Abstract A105: Identification of gene expression profiles associated with different types of breast adipose and their relationship to tumorigenesis

Abstract Background: Research over the past decade has shown the importance of the stroma in tumorigenesis, however, having long been thought to function only as an inert energy storage depot, the role of adipose tissue in tumor etiology has been largely ignored. Improved understanding of the role of adipose in tumor development and progression is crucial given the increasing rates of obesity and the use of autologous fat transfer in breast reconstruction. Methods: Adipose, adjacent to and distant from invasive breast tumors, was laser microdissected from 20 post-menopausal women, and from 20 post-menopausal women with non-malignant breast disease. Gene expression data were generated using U133 2.0 microarrays. After quality control and visualization steps, the data were analyzed to identify significant patterns of differential expression between adipose classes, at the individual gene and molecular pathway level. A subset of genes were further analyzed by qRT-PCR in out-of-sample adipose specimens. Results: Pathway analysis revealed significant differences in immune response between non-malignant, distant and tumor adjacent adipose. 141 genes were differentially expressed (FDR &amp;lt;0.05, &amp;gt;2-fold difference) between tumor-adjacent and non-malignant breasts including FCGR2A, FOLR2, LGMN and NLRP3. These four genes were also differentially expressed (FDR &amp;lt;0.05, &amp;gt;2-fold difference) between distant and non-malignant adipose. Within invasive breasts, no genes were differentially expressed using FDR &amp;lt;0.05, however, RRM2, PLA2G7, MMP9, MMP12, CHI3L1, SPP1 were expressed at &amp;gt;3-fold higher levels (P&amp;lt;0.05) in tumor-adjacent compared to distant adipose. Conclusions: Gene expression levels differ in breast adipose, depending on presence of or proximity to tumor cells. Tumor-adjacent and distant adipose from invasive breasts both exhibit increased expression in genes involved in the M2 anti-inflammatory response, suggesting that the microenvironment in an invasive breast has a decreased immune response compared to the non-malignant microenvironment. Genes expressed at higher levels in tumor-adjacent compared to distant adipose are associated with increased cellular proliferation, invasion, migration, angiogenesis and metastasis, suggesting that tumor-adjacent adipose promotes the growth and progression of the tumor. Together, these data suggest that adipose is not an inert component of the breast microenvironment but plays an active role in tumorigenesis. Citation Format: Lori Field, Brenda Deyarmin, Ryan van Laar, Craig Shriver, Rachel Ellsworth. Identification of gene expression profiles associated with different types of breast adipose and their relationship to tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A105.</jats:p

Abstract 4266: Identification of gene expression profiles associated with different types of breast adipose and their relationship to tumorigenesis

Abstract Background: Research over the past decade has shown the importance of the stroma in tumorigenesis, however, having long been thought to function only as an inert energy storage depot, the role of adipose tissue in tumorigenesis has been largely ignored. Improved understanding of the role of adipose in tumorigenesis is crucial given the increasing rates of obesity and the use of autologous fat transfer in breast reconstruction. Methods: Adipose, adjacent to and distant from invasive breast tumors, was laser microdissected from 20 post-menopausal women, and from 20 post-menopausal women with non-malignant breast disease. Gene expression data were generated using U133 2.0 microarrays. After quality control and visualization steps, the data were analyzed to identify significant patterns of differential expression between adipose classes, at the individual gene and molecular pathway level. Results: Pathway analysis revealed that immune response differs between non-malignant, distant and tumor adjacent adipose; this response is seen as a gradient with the largest response closest to the tumor. Gene expression differed significantly in adipose from invasive compared to non-malignant breasts with FCGR2A, FOLR2, LGMN, MARCO and NLRP3 expressed at significantly higher levels and HLA-DQB1 and HLA-DQA1 at significantly lower levels in adipose from invasive breasts. Within the invasive breasts, MMP9, PLA2G7, RRM2 and SPP1 were expressed at &amp;gt;3-fold higher levels in adjacent compared to distant adipose. Conclusions: Gene expression levels differ in breast adipose, depending on presence of or proximity to tumor cells. Adipose adjacent to the tumor demonstrated the largest immune response; this response may reflect a reaction to surgical insult from the original biopsy; however, response to surgical injury has been associated with increased ability to metastasize. In addition, within breasts with invasive breast cancer, genes involved in cellular proliferation, degradation of the extracellular matrix and angiogenesis were expressed at higher levels in adjacent compared to distant adipose. Together, these data suggest that adipose is not an inert component of the breast microenvironment but plays an active role in tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4266. doi:1538-7445.AM2012-4266</jats:p