Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

AbstractEndometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.

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Hormone receptor expression patterns define clinically meaningful subgroups of endometrioid ovarian carcinoma

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.09.001 ◽

2019 ◽

Vol 155 (2) ◽

pp. 318-323 ◽

Cited By ~ 3

Author(s):

Robert L. Hollis ◽

Barbara Stanley ◽

Yasushi Iida ◽

John Thomson ◽

Michael Churchman ◽

...

Keyword(s):

Ovarian Carcinoma ◽

Hormone Receptor ◽

Expression Patterns ◽

Receptor Expression ◽

Endometrioid Ovarian Carcinoma ◽

Hormone Receptor Expression

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Single-Cell RNA Sequencing Unveils Unique Transcriptomic Signatures of Organ-Specific Endothelial Cells

Circulation ◽

10.1161/circulationaha.119.041433 ◽

2020 ◽

Vol 142 (19) ◽

pp. 1848-1862 ◽

Cited By ~ 1

Author(s):

David T. Paik ◽

Lei Tian ◽

Ian M. Williams ◽

Siyeon Rhee ◽

Hao Zhang ◽

...

Keyword(s):

Endothelial Cells ◽

Single Cell ◽

Rna Sequencing ◽

Expression Patterns ◽

Receptor Expression ◽

Transcriptional Networks ◽

Sequencing Data ◽

Tissue Specific ◽

Functional Relationships ◽

Single Cell Rna Sequencing

Background: Endothelial cells (ECs) display considerable functional heterogeneity depending on the vessel and tissue in which they are located. Whereas these functional differences are presumably imprinted in the transcriptome, the pathways and networks that sustain EC heterogeneity have not been fully delineated. Methods: To investigate the transcriptomic basis of EC specificity, we analyzed single-cell RNA sequencing data from tissue-specific mouse ECs generated by the Tabula Muris consortium. We used a number of bioinformatics tools to uncover markers and sources of EC heterogeneity from single-cell RNA sequencing data. Results: We found a strong correlation between tissue-specific EC transcriptomic measurements generated by either single-cell RNA sequencing or bulk RNA sequencing, thus validating the approach. Using a graph-based clustering algorithm, we found that certain tissue-specific ECs cluster strongly by tissue (eg, liver, brain), whereas others (ie, adipose, heart) have considerable transcriptomic overlap with ECs from other tissues. We identified novel markers of tissue-specific ECs and signaling pathways that may be involved in maintaining their identity. Sex was a considerable source of heterogeneity in the endothelial transcriptome and we discovered Lars2 to be a gene that is highly enriched in ECs from male mice. We found that markers of heart and lung ECs in mice were conserved in human fetal heart and lung ECs. We identified potential angiocrine interactions between tissue-specific ECs and other cell types by analyzing ligand and receptor expression patterns. Conclusions: We used single-cell RNA sequencing data generated by the Tabula Muris consortium to uncover transcriptional networks that maintain tissue-specific EC identity and to identify novel angiocrine and functional relationships between tissue-specific ECs.

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Canine tumor mutation rate is positively correlated with TP53 mutation across cancer types and breeds

10.1101/2020.07.15.205286 ◽

2020 ◽

Author(s):

Burair A. Alsaihati ◽

Kun-Lin Ho ◽

Joshua Watson ◽

Yuan Feng ◽

Tianfang Wang ◽

...

Keyword(s):

Mutation Rate ◽

Mammary Cancer ◽

Mutation Rates ◽

Cancer Type ◽

Sequencing Data ◽

Major Pathway ◽

Molecular Features ◽

Oral Melanoma ◽

Whole Exome Sequencing Data ◽

Cancer Types

AbstractSpontaneous canine cancers are a valuable but relatively understudied and underutilized model in cancer research. To enhance their usage, we reanalyzed whole exome sequencing data published for 601 dogs with mammary cancer, osteosarcoma, oral melanoma, lymphoma, glioma or hemangiosarcoma from over 35 breeds, after rigorous quality control, including breed validation. Each cancer type harbors distinct molecular features, with major pathway alterations matching its human counterpart (e.g., PI3K for mammary cancer and p53 for osteosarcoma). On average, mammary cancer and glioma have lower mutation rates (median <0.5 mutation per Mb), whereas oral melanoma, osteosarcoma and hemangiosarcoma have higher mutation rates (median ≥1 mutation per Mb). Across cancer types and across breeds, the mutation rate is strongly associated with TP53 mutation, but not with PIK3CA mutation. The mutation rate is also associated with a mutation signature enriched in osteosarcoma of Golden Retrievers, independent of TP53 mutation. Finally, compared to other breeds examined, DNA repair genes appear to be less conserved in Golden Retriever which is predisposed to numerous cancers.

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Faculty Opinions recommendation of Cell surface receptor expression patterns in osteosarcoma.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13200010.14542130 ◽

2011 ◽

Author(s):

Maria Michelagnoli ◽

Harriet Holme

Keyword(s):

Cell Surface ◽

Expression Patterns ◽

Receptor Expression ◽

Cell Surface Receptor ◽

Surface Receptor

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Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽

10.3390/biom11050750 ◽

2021 ◽

Vol 11 (5) ◽

pp. 750

Author(s):

Kiyohiro Ando ◽

Akira Nakagawara

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Mitotic Catastrophe ◽

Malignant Neoplasms ◽

Checkpoint Kinases ◽

Molecular Features ◽

Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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Differential expression and correlation analysis of miRNA–mRNA profiles in swine testicular cells infected with porcine epidemic diarrhea virus

Scientific Reports ◽

10.1038/s41598-021-81189-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaoqian Zhang ◽

Chang Li ◽

Bingzhou Zhang ◽

Zhonghua Li ◽

Wei Zeng ◽

...

Keyword(s):

Differential Expression ◽

Porcine Epidemic Diarrhea Virus ◽

Expression Profiles ◽

Expression Patterns ◽

Bacterial Invasion ◽

Sequencing Data ◽

Diarrhea Virus ◽

Comparison Groups ◽

Porcine Epidemic Diarrhea

AbstractThe variant virulent porcine epidemic diarrhea virus (PEDV) strain (YN15) can cause severe porcine epidemic diarrhea (PED); however, the attenuated vaccine-like PEDV strain (YN144) can induce immunity in piglets. To investigate the differences in pathogenesis and epigenetic mechanisms between the two strains, differential expression and correlation analyses of the microRNA (miRNA) and mRNA in swine testicular (ST) cells infected with YN15, YN144, and mock were performed on three comparison groups (YN15 vs Control, YN144 vs Control, and YN15 vs YN144). The mRNA and miRNA expression profiles were obtained using next-generation sequencing (NGS), and the differentially expressed (DE) (p-value < 0.05) mRNA and miRNA were obtained using DESeq R package. mRNAs targeted by DE miRNAs were predicted using the miRanda algortithm. 8039, 8631 and 3310 DE mRNAs, and 36, 36, and 22 DE miRNAs were identified in the three comparison groups, respectively. 14,140, 15,367 and 3771 DE miRNA–mRNA (targeted by DE miRNAs) interaction pairs with negatively correlated expression patterns were identified, and interaction networks were constructed using Cytoscape. Six DE miRNAs and six DE mRNAs were randomly selected to verify the sequencing data by real-time relative quantitative reverse transcription polymerase chain reaction (qRT-PCR). Based on bioinformatics analysis, we discovered the differences were mostly involved in host immune responses and viral pathogenicity, including NF-κB signaling pathway and bacterial invasion of epithelial cells, etc. This is the first comprehensive comparison of DE miRNA–mRNA pairs in YN15 and YN144 infection in vitro, which could provide novel strategies for the prevention and control of PED.

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Neoplastic cellularity is associated with clinical and molecular features of high-grade serous ovarian carcinoma

Gynecologic Oncology ◽

10.1016/j.ygyno.2015.07.063 ◽

2015 ◽

Vol 139 (1) ◽

pp. 196

Author(s):

C. Morse ◽

B. Norquist ◽

S. Bernards ◽

M. Harrell ◽

K. Agnew ◽

...

Keyword(s):

Ovarian Carcinoma ◽

High Grade ◽

Molecular Features ◽

Serous Ovarian Carcinoma

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Hyaluronan-mediated motility receptor expression functions as a prognostic biomarker in uterine carcinosarcoma based on bioinformatics analysis

Journal of International Medical Research ◽

10.1177/03000605211021043 ◽

2021 ◽

Vol 49 (6) ◽

pp. 030006052110210

Author(s):

Hui Sun ◽

Li Ma ◽

Jie Chen

Keyword(s):

Interaction Network ◽

Maximal Clique ◽

Receptor Expression ◽

The Cancer Genome Atlas ◽

Uterine Carcinosarcoma ◽

Sequencing Data ◽

Hub Genes ◽

Protein Protein Interaction ◽

Normal Tissues ◽

Potential Biomarker

Objective Uterine carcinosarcoma (UCS) is a rare, aggressive tumour with a high metastasis rate and poor prognosis. This study aimed to explore potential key genes associated with the prognosis of UCS. Methods Transcriptional expression data were downloaded from the Gene Expression Profiling Interactive Analysis database and differentially expressed genes (DEGs) were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses using Metascape. A protein–protein interaction network was constructed using the STRING website and Cytoscape software, and the top 30 genes obtained through the Maximal Clique Centrality algorithm were selected as hub genes. These hub genes were validated by clinicopathological and sequencing data for 56 patients with UCS from The Cancer Genome Atlas database. Results A total of 1894 DEGs were identified, and the top 30 genes were considered as hub genes. Hyaluronan-mediated motility receptor (HMMR) expression was significantly higher in UCS tissues compared with normal tissues, and elevated expression of HMMR was identified as an independent prognostic factor for shorter survival in patients with UCS. Conclusions These results suggest that HMMR may be a potential biomarker for predicting the prognosis of patients with UCS.

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