Differential expression of H2A isoforms contribute to tissue and lineage specificity with HIST2H2AC as a potential cancer biomarker

AbstractRecent advancements in the field of histone biology imply non-redundancy in the function of histone H2A isoforms; however, the expression of H2A isoforms in various normal tissue types, the correlation among organs and tumor/tumor type-specific expression remain poorly investigated. The profiling of sixteen H2A isoforms in eleven different normal human tissue types strongly suggests their tissue-specific or predominant expression. Further, clustering analysis shows a lineage-specific correlation of H2A isoforms. In continuation, the expression analysis in twelve human tumor types shows overexpression of HIST2H2AC. Moreover, overexpression was observed exclusively in tumor samples but not with fetal samples; highlighting the cancer-specific association of HIST2H2AC. Further, in silico analysis of TCGA pan-cancer data also showed tumor-specific over-expression of the HIST2H2AC isoform. Our findings provide insights into tissue-type-specificity of histone H2A isoforms expression patterns and advance our understanding of their importance in lineage specification and cancer.

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An Integrative Analysis of microRNA and mRNA Expression–-A Case Study

Cancer Informatics ◽

10.4137/cin.s633 ◽

2008 ◽

Vol 6 ◽

pp. CIN.S633 ◽

Cited By ~ 15

Author(s):

Li-Xuan Qin

Keyword(s):

Gene Expression ◽

Mrna Expression ◽

Hierarchical Clustering ◽

Human Cancer ◽

Microrna Expression ◽

Tissue Type ◽

Integrated Analysis ◽

Tumor Type ◽

Cancer Data

Background MicroRNAs are believed to play an important role in gene expression regulation. They have been shown to be involved in cell cycle regulation and cancer. MicroRNA expression profiling became available owing to recent technology advancement. In some studies, both microRNA expression and mRNA expression are measured, which allows an integrated analysis of microRNA and mRNA expression. Results We demonstrated three aspects of an integrated analysis of microRNA and mRNA expression, through a case study of human cancer data. We showed that (1) microRNA expression efficiently sorts tumors from normal tissues regardless of tumor type, while gene expression does not; (2) many microRNAs are down-regulated in tumors and these microRNAs can be clustered in two ways: microRNAs similarly affected by cancer and microRNAs similarly interacting with genes; (3) taking let-7f as an example, targets genes can be identified and they can be clustered based on their relationship with let-7f expression. Discussion Our findings in this paper were made using novel applications of existing statistical methods: hierarchical clustering was applied with a new distance measure–the co-clustering frequency–to identify sample clusters that are stable; microRNA-gene correlation profiles were subject to hierarchical clustering to identify microRNAs that similarly interact with genes and hence are likely functionally related; the clustering of regression models method was applied to identify microRNAs similarly related to cancer while adjusting for tissue type and genes similarly related to microRNA while adjusting for disease status. These analytic methods are applicable to interrogate multiple types of -omics data in general.

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Real-world data validation for differential expression of immunoregulatory molecules and targetable cancer genes may provide therapeutic insights into agnostic-driven trial designs.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.10 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 10-10 ◽

Cited By ~ 1

Author(s):

Jacob J. Adashek ◽

Christopher W. Szeto ◽

Sandeep K. Reddy ◽

Philippe E. Spiess

Keyword(s):

Differential Expression ◽

Real World ◽

Treatment Options ◽

Expression Patterns ◽

Gene Mutations ◽

Tissue Type ◽

Tumor Type ◽

Cancer Genes ◽

Real World Data ◽

External Database

10 Background: Targeting actionable genes and using immunotherapy have increased treatment options. We previously reported that some immunoregulatory molecules are found differentially regulated in the presence of certain gene mutations regardless of cancer subtype. Here we validated a subset of these associations in an independent, real-world dataset with distinct clinicopathological characteristics. Methods: Previously, 2740 TCGA patients were identified to have at least one potentially oncogenic mutation (mt) within an established 50-gene hotspot panel. Differential expression of 10 immunoregulatory molecules (IRM) was analyzed between mutant (mt) vs. wild-type (wt). To ensure observed significant associations were not confounded by tumor-type, differential IRM expression within mt-enriched tumor-types was compared to that of mt vs. wt. Now, using the NantHealth external database of 2739 unselected clinical cases these associations were validated. Results: Within the TCGA cohort 19/50 gene mutations were found to be significantly associated with ≥1 IRM expression. In many, the mt effect-size was larger than that of tumor-type; e.g. head & neck carcinomas (HNSCC) are highly enriched for CDKN2A mt (OR = 4.9, p = 4.3e-9), yet CDKN2A mt are more associated with CTLA4 expression than HNSCC histology (t = 7.0 vs. 5.4). Of these 15 associations, 6 were validated within the independent later-stage NantHealth cohort. Most notably, CDKN2A mt was validated as associated with increased PD1 and CTLA4 expression while KRAS and APC mt were validated as associated with decreased PDL1/2 expression. Conclusions: The presented differential checkpoint expression patterns are strongly associated with mutation status and are not primarily driven by tissue-type, which have been further validated by an external database. Strategies combining genomic targets have been shown to yield success as well as using immunotherapies. Our data suggests there may be a role for combining NGS targets along with IRM expression patterns to better guide future design of clinical trials in combatting various cancers in a tissue-agnostic fashion.

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Analysis of expression of TGF-β1 receptor (ALK-1) in normal and tumor tissues by tissue microarrays

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22044 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22044-e22044

Author(s):

A. Erbersdobler ◽

R. Simon ◽

O. J. Hellwinkel ◽

C. Bokemeyer ◽

G. Sauter ◽

...

Keyword(s):

Female Genital Tract ◽

Human Tumor ◽

Class I ◽

Angiogenic Factor ◽

Tissue Type ◽

Knock Out ◽

Tissue Arrays ◽

Tumor Tissues ◽

Tumor Types ◽

Tgf Β1

e22044 Background: TGF-β1 is an important angiogenic factor involved in different aspects of angiogenesis and vessel maintenance. TGF-β1 receptors consist of class I, class II and accessory receptors. Activin-like kinase I (ALK-1) is a class I TGF- β1 receptor which is almost exclusively expressed on endothelial cells. Hereditary hemorrhagic telangiectasia (HHT) is caused by mutations in the ALK-1 gene. Knock-out mice for ALK-1 die during gestation due to vascular malformation. ALK-1 may thus represent an attractive target for anti-angiogenic therapy. A therapeutic monoclonal antibody (PF-03446962) against ALK-1 has been developed which is currently in phase I testing. Here we describe target validation in normal and tumor tissue using tissue micro-arrays (TMAs). Methods: Normal tissue arrays comprised of 609 individual histological samples representing 76 human tissues. Multi-tumor arrays consisted of 3923 individual tumor samples from 87 tumor types. Consecutive sections of tissue arrays were stained for ALK-1 and CD31. CD31 immunohistology (IHC) was performed to ensure presence of vessels within tissue samples. ALK-1 staining was graded 0=absent, 1=weak, 2= moderate and 3=strong by an experienced pathologist blinded to tissue type. Results: ALK-1 staining of vessels in normal tissues was generally weak (mostly grade 1 and rarely grade 2) and was detectable in lymphatic tissues including tonsil, lymph nodes, thymus and spleen, lung, the entire GI tract including parotid, submandibular and sublingual glands as well as pancreas. ALK-1 positive vessels were also found within the female genital tract including placenta, uterus and ovary. In human tumor vessels ALK-1 expression showed high variability between tumor types. The highest ALK-1 expression rate was found in lung cancer (NSCLC 49%, SCLC 83%), neuroendocrine pancreas tumor (71%), colon cancer (50%), chondrosarcoma 50%, angiosarcoma 40% and NHL (44%). Conclusions: TMAs are an excellent tool to verify target expression in normal and tumor tissues. Results may be used to predict side effects of targeted therapy and to direct phase II testing of innovative agents in patients likely to respond. [Table: see text]

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Tissue-specific expression of the fibril-associated collagens XII and XIV

Journal of Cell Science ◽

10.1242/jcs.107.2.669 ◽

1994 ◽

Vol 107 (2) ◽

pp. 669-681 ◽

Cited By ~ 4

Author(s):

C. Walchli ◽

M. Koch ◽

M. Chiquet ◽

B.F. Odermatt ◽

B. Trueb

Keyword(s):

Embryonic Development ◽

Type I Collagen ◽

Expression Patterns ◽

Collagen Fibrils ◽

Tissue Type ◽

Type I ◽

Connective Tissues ◽

Specific Expression ◽

Temporal Regulation ◽

Fibrillar Collagens

Interstitial collagen fibrils form the supporting scaffold of all connective tissues. The synthesis of this framework is subject to a precise spatial and temporal regulation in order to meet the mechanical needs of every tissue type. A subgroup of non-fibrillar collagens termed FACIT seems to play a role in this regulation by providing specific molecular bridges between fibrils and other matrix components. Collagens XII and XIV represent such FACIT molecules and occur preferentially in tissues containing banded type I collagen fibrils. We have used the techniques of indirect immunofluorescence and in situ hybridization to investigate the expression patterns of the two molecules during chicken embryonic development. We detected specific differences in these patterns, which may be related to the respective functions of the two proteins within the connective tissues. Collagen XIV was expressed at very few sites in the 6-day-old embryo, but occurred in virtually every collagen I-containing tissue (skeletal muscle, cardiac muscle, gizzard, tendon, periosteum, nerve) by the end of embryonic development. In contrast, collagen XII was fairly abundant in the 6-day-old embryo but was, at later stages, restricted to only a few dense connective tissue structures (bone, tendon, gizzard). Thus, our results suggest that collagen XII and collagen XIV serve different functions during embryonic development although their structures are highly similar.

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Recurrently deregulated lncRNAs associated with HCC tumorigenesis and metastasis revealed by genomic, epigenomic, and transcriptomic profiling in paired primary tumor and PVTT samples

10.1101/050377 ◽

2016 ◽

Author(s):

Yang Yang ◽

Lei Chen ◽

Jin Gu ◽

Hanshuo Zhang ◽

Jiapei Yuan ◽

...

Keyword(s):

Primary Tumor ◽

Expression Patterns ◽

Copy Number Variations ◽

Intrahepatic Metastasis ◽

Clinical Samples ◽

Loss Of Function ◽

Specific Expression ◽

Cancer Data ◽

Novel Biomarkers

AbstractHepatocellular carcinoma (HCC) are highly potent to invade the portal venous system and subsequently develop into the portal vein tumor thrombosis (PVTT). PVTT could induce intrahepatic metastasis, which is closely associated with poor prognosis. A comprehensive systematic characterization of long noncoding RNAs (lncRNAs) associated with HCC metastasis has not been reported. Here, we first assayed 60 clinical samples (matched primary tumor, adjacent normal tissue, and PVTT) from 20 HCC patients using total RNA sequencing. We identified and characterized 8,603 novel lncRNAs from 9.6 billion sequenced reads, indicating specific expression of these lncRNAs in our samples. On the other hand, the expression patterns of 3,212 known and novel recurrently deregulated lncRNAs (in >=20% of our patients) were well correlated with clinical data in a TCGA cohort and published liver cancer data. Some lncRNAs (e.g., RP11-166D19.1/MIR100HG) were shown to be useful as putative biomarkers for prognosis and metastasis. Moreover, matched array data from 60 samples showed that copy number variations (CNVs) and alterations in DNA methylation contributed to the observed recurrent deregulation of 716 lncRNAs. Subsequently, using a coding-noncoding co-expression network, we found that many recurrently deregulated lncRNAs were enriched in clusters of genes related to cell adhesion, immune response, and metabolic processes. Candidate lncRNAs related to metastasis, such as HAND2-AS1, were further validated using RNAi-based loss-of-function assays. The results of our integrative analysis provide a valuable resource regarding functional lncRNAs and novel biomarkers associated with HCC tumorigenesis and metastasis.

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The Role of 5-HT1A Receptor in Cancer as a New Opportunity in Medicinal Chemistry

Current Medicinal Chemistry ◽

10.2174/0929867325666180209141650 ◽

2018 ◽

Vol 25 (27) ◽

pp. 3214-3227 ◽

Cited By ~ 7

Author(s):

Angela Corvino ◽

Ferdinando Fiorino ◽

Beatrice Severino ◽

Irene Saccone ◽

Francesco Frecentese ◽

...

Keyword(s):

Serotonin Receptor ◽

Pain Treatment ◽

Neurological Diseases ◽

Human Tumor ◽

Receptor Subtype ◽

Tumor Type ◽

Malignant Carcinoid ◽

Malignant Carcinoid Syndrome ◽

Tumor Types

The 5-HT1A receptor is a pharmacologically well characterized serotonin receptor subtype and it has long been investigated because of its involvement in several physiopathological mechanisms and treatment of neurological diseases like ansia and depression. Serotonin (5-HT) also shows many non-neural functions such as essential hypertension, embryogenesis, follicle maturation and behavior. Moreover, it exerts a growth factor function on different types of non-tumoral cells, and it was also found to be related to oncogenes. In fact, growth-stimulatory activity of serotonin in different human tumor cells has been reported. Recently, new chemical molecules binding the 5-HT1A receptor have been described as novel therapeutic entities useful in neuroprotection, cognitive impairment, Parkinson’s Disease, pain treatment, malignant carcinoid syndrome and cancer. It was widely demonstrated that 5-HT1A receptor is involved in the carcinogenesis and consequently in many human tumor types, such as prostate, bladder, small cell lung, colonrectal and cholangiocarcinoma. Furthermore, depending on the tumor type, 5-HT1A receptor antagonists were shown to be capable of blocking the 5HT-induced increase in tumor growth. In this review, we have focused our attention on each tumor type where the 5-HT1A receptor is involved, investigating the role of this molecular target and the different classes of compounds that have shown the capability to modulate it. The analyzed aspects could represent a hint for the medical chemists to develop novel molecules as selective 5-HT1A agents are useful in further elucidating the role of this therapeutic target.

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The human tumor microbiome is composed of tumor type–specific intracellular bacteria

Science ◽

10.1126/science.aay9189 ◽

2020 ◽

Vol 368 (6494) ◽

pp. 973-980 ◽

Cited By ~ 60

Author(s):

Deborah Nejman ◽

Ilana Livyatan ◽

Garold Fuks ◽

Nancy Gavert ◽

Yaara Zwang ◽

...

Keyword(s):

Smoking Status ◽

Human Tumor ◽

Comprehensive Analysis ◽

Intracellular Bacteria ◽

Tumor Type ◽

Microbiome Composition ◽

Normal Tissues ◽

Cancer Types ◽

Tumor Types

Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients’ smoking status, and the response to immunotherapy.

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WormCat 2.0 defines characteristics and conservation of poorly annotated genes in Caenorhabditis elegans

10.1101/2021.11.11.467968 ◽

2021 ◽

Author(s):

Daniel Patrick Higgins ◽

Caroline M Weisman ◽

Dominique S Lui ◽

Frank A D'Agostino ◽

Amy Karol Walker

Keyword(s):

Caenorhabditis Elegans ◽

Expression Patterns ◽

Functional Study ◽

Data Sets ◽

Specific Expression ◽

Protein Levels ◽

Human Genes ◽

Human Orthologs ◽

Lineage Specificity ◽

Gene Category

Genome-wide measurement of mRNA or protein levels provides broad data sets for biological discovery. However, subsequent computational methods are essential for uncovering the functional implications of the data as well as intuitively visualizing the findings. Current computational tools are biased toward well-described pathways, limiting their utility for novel discovery. Recently, we developed an annotation and category enrichment tool for Caenorhabditis elegans genomic data, WormCat, that provides an intuitive visualization output. Unlike GO, which excludes genes with no annotation information retains these genes as a special UNASSIGNED category. Here, we show that the UNASSIGNED gene category shows tissue-specific expression patterns and include genes with biological functions. Poorly annotated genes have previously been considered to lack homologs in closely related species. Instead, we find that around 3% of the UNASSIGNED genes have poorly characterized human orthologs. These human orthologs are themselves poorly characterized. A recently developed method that incorporates lineage relationships (abSENSE) indicates that failure of BLAST to detect homology explains the apparent lineage specificity for many UNASSIGNED genes, suggesting that a larger subset could be related to human genes. WormCat provides an annotation strategy that allows association of UNASSIGNED genes with specific phenotypes and known pathways. Our analysis indicates that the UNASSIGNED gene category contains candidates that merit further functional study which could yield insight into understudied areas of biology.

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Ultrastructure of two neoplasms in culture compared with original biopsies

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100110623 ◽

1984 ◽

Vol 42 ◽

pp. 50-51

Author(s):

Joseph M. Harb ◽

James T. Casper ◽

Vlcki Piaskowski

Keyword(s):

Electron Microscopy ◽

Tissue Culture ◽

Biopsy Specimen ◽

Cultured Cells ◽

Light And Electron Microscopy ◽

Human Tumor ◽

Soft Agar ◽

Human Tumor Cells ◽

Morphological Distinction ◽

Tumor Types

The application of tissue culture and the newer methodologies of direct cloning and colony formation of human tumor cells in soft agar hold promise as valuable modalities for a variety of diagnostic studies, which include morphological distinction between tumor types by electron microscopy (EM). We present here two cases in which cells in culture expressed distinct morphological features not apparent in the original biopsy specimen. Evaluation of the original biopsies by light and electron microscopy indicated both neoplasms to be undifferentiated sarcomas. Colonies of cells propagated in soft agar displayed features of rhabdomyoblasts in one case, and cultured cells of the second biopsy expressed features of Ewing's sarcoma.

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