Tertiary lymphoid structure stratifies glioma into three distinct tumor subtypes

Abstract Molecular classification of glioblastoma has enabled a deeper understanding of the disease. The four-subtype model (including Proneural, Classical, Mesenchymal and Neural) has been replaced by a model that discards the Neural subtype, found to be associated with samples with a high content of normal tissue. These samples can be misclassified preventing biological and clinical insights into the different tumor subtypes from coming to light. In this work, we present a model that tackles both the molecular classification of samples and discrimination of those with a high content of normal cells. We performed a transcriptomic in silico analysis on glioblastoma (GBM) samples (n = 810) and tested different criteria to optimize the number of genes needed for molecular classification. We used gene expression of normal brain samples (n = 555) to design an additional gene signature to detect samples with a high normal tissue content. Microdissection samples of different structures within GBM (n = 122) have been used to validate the final model. Finally, the model was tested in a cohort of 43 patients and confirmed by histology. Based on the expression of 20 genes, our model is able to discriminate samples with a high content of normal tissue and to classify the remaining ones. We have shown that taking into consideration normal cells can prevent errors in the classification and the subsequent misinterpretation of the results. Moreover, considering only samples with a low content of normal cells, we found an association between the complexity of the samples and survival for the three molecular subtypes.

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Molecular Tumor Subtypes of HPV-Positive Head and Neck Cancers: Biological Characteristics and Implications for Clinical Outcomes

Cancers ◽

10.3390/cancers13112721 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2721

Author(s):

Tingting Qin ◽

Shiting Li ◽

Leanne E. Henry ◽

Siyu Liu ◽

Maureen A. Sartor

Keyword(s):

Head And Neck ◽

Stromal Cells ◽

Clinical Characteristics ◽

Molecular Subtypes ◽

Squamous Cell Carcinomas ◽

Head And Neck Cancers ◽

Molecular Signatures ◽

Tumor Subtypes ◽

Mesenchymal Differentiation ◽

High Incidence

Until recently, research on the molecular signatures of Human papillomavirus (HPV)-associated head and neck cancers mainly focused on their differences with respect to HPV-negative head and neck squamous cell carcinomas (HNSCCs). However, given the continuing high incidence level of HPV-related HNSCC, the time is ripe to characterize the heterogeneity that exists within these cancers. Here, we review research thus far on HPV-positive HNSCC molecular subtypes, and their relationship with clinical characteristics and HPV integration into the host genome. Different omics data including host transcriptomics and epigenomics, as well as HPV characteristics, can provide complementary viewpoints. Keratinization, mesenchymal differentiation, immune signatures, stromal cells and oxidoreductive processes all play important roles.

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Ovarian sex cord-stromal tumors: an update on clinical features, molecular changes, and management

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-002018 ◽

2021 ◽

pp. ijgc-2020-002018

Author(s):

Rehab Al Harbi ◽

Iain A McNeish ◽

Mona El-Bahrawy

Keyword(s):

Hormonal Therapy ◽

Clinical Presentation ◽

Therapeutic Modality ◽

Biological Behavior ◽

Molecular Changes ◽

Histological Features ◽

Stromal Tumors ◽

Tumor Subtypes ◽

Tumor Types ◽

Sex Cord Stromal Tumors

Sex cord stromal-tumors are rare tumors of the ovary that include numerous tumor subtypes of variable histological features and biological behavior. Surgery is the main therapeutic modality for the management of these tumors, while chemotherapy and hormonal therapy may be used in some patients with progressive and recurrent tumors. Several studies investigated molecular changes in the different tumor types. Understanding molecular changes underlying the development and progression of sex cord-stromal tumors provides valuable information for diagnostic and prognostic biomarkers and potential therapeutic targets for these tumors. In this review, we provide an update on the clinical presentation, molecular changes, and management of sex cord-stromal tumors.

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Pan-cancer characterization of lncRNA modifiers of immune microenvironment reveals clinically distinct de novo tumor subtypes

npj Genomic Medicine ◽

10.1038/s41525-021-00215-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Zicheng Zhang ◽

Congcong Yan ◽

Ke Li ◽

Siqi Bao ◽

Lei Li ◽

...

Keyword(s):

Noncoding Rna ◽

Immune Cell ◽

De Novo ◽

Solid Cancer ◽

Immune Microenvironment ◽

Cancer Subtypes ◽

Tumor Subtypes ◽

Cancer Immunity ◽

Systems Immunology ◽

Pan Cancer

AbstractThe emerging field of long noncoding RNA (lncRNA)-immunity has provided a new perspective on cancer immunity and immunotherapies. The lncRNA modifiers of infiltrating immune cells in the tumor immune microenvironment (TIME) and their impact on tumor behavior and disease prognosis remain largely uncharacterized. In the present study, a systems immunology framework integrating the noncoding transcriptome and immunogenomics profiles of 9549 tumor samples across 30 solid cancer types was used, and 36 lncRNAs were identified as modifier candidates underlying immune cell infiltration in the TIME at the pan-cancer level. These TIME lncRNA modifiers (TIL-lncRNAs) were able to subclassify various tumors into three de novo pan-cancer subtypes characterized by distinct immunological features, biological behaviors, and disease prognoses. Finally, a TIL-lncRNA-derived immune state index (TISI) that was reflective of immunological and oncogenic states but also predictive of patients’ prognosis was proposed. Furthermore, the TISI provided additional prognostic value for existing tumor immunological and molecular subtypes. By applying the TISI to tumors from different clinical immunotherapy cohorts, the TISI was found to be significantly negatively correlated with immune-checkpoint genes and to have the ability to predict the effectiveness of immunotherapy. In conclusion, the present study provided comprehensive resources and insights for future functional and mechanistic studies on lncRNA-mediated cancer immunity and highlighted the potential of the clinical application of lncRNA-based immunotherapeutic strategies in precision immunotherapy.

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Differential Expression of Peroxisomal Proteins in Distinct Types of Parotid Gland Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22157872 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7872

Author(s):

Malin Tordis Meyer ◽

Christoph Watermann ◽

Thomas Dreyer ◽

Steffen Wagner ◽

Claus Wittekindt ◽

...

Keyword(s):

Redox Balance ◽

Matrix Proteins ◽

Parotid Tumor ◽

Gene Expressions ◽

Tissue Samples ◽

Cellular Redox ◽

Tumor Subtypes ◽

Parotid Tumors ◽

Aggressive Tumors

Salivary gland cancers are rare but aggressive tumors that have poor prognosis and lack effective cure. Of those, parotid tumors constitute the majority. Functioning as metabolic machinery contributing to cellular redox balance, peroxisomes have emerged as crucial players in tumorigenesis. Studies on murine and human cells have examined the role of peroxisomes in carcinogenesis with conflicting results. These studies either examined the consequences of altered peroxisomal proliferators or compared their expression in healthy and neoplastic tissues. None, however, examined such differences exclusively in human parotid tissue or extended comparison to peroxisomal proteins and their associated gene expressions. Therefore, we examined differences in peroxisomal dynamics in parotid tumors of different morphologies. Using immunofluorescence and quantitative PCR, we compared the expression levels of key peroxisomal enzymes and proliferators in healthy and neoplastic parotid tissue samples. Three parotid tumor subtypes were examined: pleomorphic adenoma, mucoepidermoid carcinoma and acinic cell carcinoma. We observed higher expression of peroxisomal matrix proteins in neoplastic samples with exceptional down regulation of certain enzymes; however, the degree of expression varied between tumor subtypes. Our findings confirm previous experimental results on other organ tissues and suggest peroxisomes as possible therapeutic targets or markers in all or certain subtypes of parotid neoplasms.

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Characterization of lung tumor subtypes through gene expression cluster validity assessment

RAIRO - Theoretical Informatics and Applications ◽

10.1051/ita:2006011 ◽

2006 ◽

Vol 40 (2) ◽

pp. 163-176 ◽

Cited By ~ 5

Author(s):

Giorgio Valentini ◽

Francesca Ruffino

Keyword(s):

Gene Expression ◽

Lung Tumor ◽

Cluster Validity ◽

Tumor Subtypes ◽

Validity Assessment ◽

Expression Cluster ◽

Gene Expression Cluster

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Expression and function of ErbB receptors and ligands in the pituitary

Endocrine Related Cancer ◽

10.1530/erc-11-0066 ◽

2011 ◽

Vol 18 (6) ◽

pp. R197-R211 ◽

Cited By ~ 42

Author(s):

Odelia Cooper ◽

George Vlotides ◽

Hidenori Fukuoka ◽

Mark I Greene ◽

Shlomo Melmed

Keyword(s):

Anterior Pituitary ◽

Kinase Inhibitors ◽

Erbb Receptors ◽

Receptor Ligands ◽

Paracrine Effects ◽

Tumor Subtypes ◽

Hormonal Secretion ◽

Gene And Protein Expression ◽

Erbb2 Receptor ◽

And Function

The role of ErbB family in discreet pituitary functions is reviewed. Several ErbB receptor ligands, EGF, TGFα, and heregulin are differentially expressed in normal gonadotroph and lacto-somatotroph lineages, and other elements of the anterior pituitary. ErbB receptors, i.e. EGFR and ErbB2, are also localized to the anterior pituitary with preferential EGFR lactosomatotroph expression. EGF regulates CRH and ACTH secretion and corticotroph proliferation as well as exhibiting autocrine and paracrine effects on gonadotrophs and on lactosomatotroph proliferation, gene and protein expression, and hormonal secretion. EGF and EGFR are expressed in both functioning and non-functioning pituitary adenomas, with higher expression in more aggressive tumor subtypes. ErbB2 receptor is detected in all tumor subtypes, particularly in invasive tumors. ErbB tyrosine kinase inhibitors regulate hormonal secretion, cell morphology, and proliferation in lacto-somatotroph tumors, reflecting the emerging application of targeted pituitary therapeutics.

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Promoter methylation of Wnt antagonistsDKK1andSFRP1is associated with opposing tumor subtypes in two large populations of colorectal cancer patients

Carcinogenesis ◽

10.1093/carcin/bgr020 ◽

2011 ◽

Vol 32 (5) ◽

pp. 741-747 ◽

Cited By ~ 52

Author(s):

James B. Rawson ◽

Michael Manno ◽

Miralem Mrkonjic ◽

Darshana Daftary ◽

Elizabeth Dicks ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Promoter Methylation ◽

Tumor Subtypes ◽

Large Populations ◽

Colorectal Cancer Patients

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Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.25.9549 ◽

2010 ◽

Vol 28 (18) ◽

pp. 2966-2973 ◽

Cited By ~ 102

Author(s):

Marco Colleoni ◽

Bernard F. Cole ◽

Giuseppe Viale ◽

Meredith M. Regan ◽

Karen N. Price ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Triple Negative ◽

Alkylating Agents ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Her2 Positive ◽

Node Negative ◽

Tumor Subtypes ◽

Node Negative Breast Cancer

Purpose Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients and Methods Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Results Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease). Conclusion The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

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