ABSTRACT
BACKGROUND: Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1-C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). METHODS: Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. RESULTS: Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-ß dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. CONCLUSIONS: The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients.
Subject(s)
Adenocarcinoma, Mucinous/classification , Adenocarcinoma/classification , Colorectal Neoplasms/classification , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/metabolism , Adenocarcinoma, Mucinous/genetics , Adenocarcinoma, Mucinous/immunology , Adenocarcinoma, Mucinous/metabolism , Aged , CD8-Positive T-Lymphocytes , Cell Proliferation/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/metabolism , Epithelial-Mesenchymal Transition/genetics , Female , Genes, MHC Class I/genetics , Humans , Inflammation/immunology , Interferon-gamma/immunology , Lymphocytes/immunology , Lymphocytes/metabolism , Macrophages/immunology , Male , Microsatellite Instability , Monocytes/immunology , Monocytes/metabolism , Neovascularization, Pathologic , Prognosis , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Receptors, Antigen, T-Cell/genetics , Signal Transduction , Th1 Cells/immunology , Th17 Cells/immunology , Th2 Cells/immunology , Transforming Growth Factor beta/immunology , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Wnt Signaling Pathway/genetics , Wound Healing/genetics , Wound Healing/immunologySubject(s)
Humans , Female , Adolescent , Metatarsalgia/complications , Metatarsalgia/diagnosis , Metatarsalgia/therapy , Diagnosis, Differential , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Cryotherapy/methods , Cryotherapy , Metatarsalgia/physiopathology , Metatarsalgia , Foot Deformities/physiopathology , Foot Deformities/therapy , Foot Deformities , Metatarsus/pathology , MetatarsusABSTRACT
The bromodomain protein BRD4 is involved in cell proliferation and cell cycle progression, primarily through its role in acetylated chromatin-dependent regulation of transcription at targeted loci. Here, we show that BRD4 is frequently downregulated by aberrant promoter hypermethylation in human colon cancer cell lines and primary tumors. Ectopic re-expression of BRD4 in these colon cancer cell lines markedly reduced in vivo tumor growth, suggesting a role of BRD4 in human colon cancer.
Subject(s)
Colonic Neoplasms/genetics , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Nuclear Proteins/genetics , Transcription Factors/genetics , Acetylation , Animals , Cell Cycle Proteins , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , DNA Methylation/genetics , Gene Silencing , Histones/metabolism , Humans , Mice , Nuclear Proteins/metabolism , Promoter Regions, Genetic/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Transcription Factors/metabolismABSTRACT
The presence of free nucleic acids in plasma has been detected in cancer patients and is associated with poor prognosis. In the present study, the mRNA levels of three genes (EPAS1, KIAA0101 and UBE2D3) in plasma from colorectal cancer patients were analyzed. These genes were selected from a previous study of genomic profiles, discriminating between healthy controls and colorectal cancer patients. mRNA levels were analyzed by real-time PCR in the plasma of 154 patients with colorectal cancer. The association of plasma mRNA levels with clinicopathological parameters and patient survival were analyzed. High levels of EPAS1 in the plasma were associated with patients aged over 50 years, relapse of disease and patient mortality. When patients were divided into two groups, early (I and II) and advanced (III and IV) stages, an association was observed between high levels of EPAS1 mRNA and worse disease-free and overall survival in advanced stages. The expression of KIAA0101 and UBE2D3 was not associated with poor prognosis. Thus, our results suggest that EPAS1 mRNA levels may be an indicator of poor prognosis in colorectal cancer patients at advanced stages, obtained by a non-invasive method.
