Prognostic value of genomic alterations in head and neck squamous cell carcinoma detected by comparative genomic hybridisation.
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ABSTRACT:
SUBMITTER: Ashman JN
PROVIDER: S-EPMC2394495 | biostudies-other | 2003 Sep
REPOSITORIES: biostudies-other
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Project description:Survival from head and neck squamous cell carcinoma (HNSCC) has remained static for the last 20 years. The development of lymph node metastasis (LNM) significantly reduces the 5-year survival rate, thus the ability to identify tumours with the potential to metastasise would allow more aggressive treatment regimes to be directed at these patients regardless of negative clinical and radiological findings at the time of presentation. Comparative genomic hybridisation (CGH) can identify chromosomal aberrations that may lead to metastasis. DNA from 23-paired specimens of primary tumour (PT) and LNM were analysed. Nonrandom copy number changes were identified in all paired samples. Similar numbers of aberrations were identified on PT and LNM samples. The most common aberrations were 3q (90%), 8q (65%), 1q (50%), 5p (43%), 2q (41%) and 11q (41%) and deletions 3p (57%), 1p (54%), 4p (48%), 13q (48%), 11q (41%) and 10q (37%). A number of differences were also detected. No aberration was found to be preferentially associated with the LNM, although gains on 6q (48 vs 22%) and 22q (26 vs 9%) were found at higher frequencies. Clonality studies demonstrated that LNM develop from the dominant population of cells in the PT. These results were compared with two similar publications. No combination of chromosomal aberrations, as detected by CGH, was associated with metastatic progression in HNSCC.
| S-EPMC2409462 | biostudies-other
Project description:Head and neck cancer collectively describes malignant tumors originating from the mucosal surface of the upper aerodigestive tract. These tumors pose a great threat to public health because of their high incidence and mortality. Traditional risk factors are tobacco and alcohol abuse. More recently, infection by high-risk types of human papilloma virus (HPV) has been identified as an additional risk factor, especially for oropharyngeal squamous cell carcinoma (OPSCC). Moreover, HPV-positive OPSCC is considered a distinct tumor entity with an improved clinical outcome compared to HPV-negative OPSCC. Epigenetic alterations act as key events in the pathogenesis of cancer and are of special interest for basic and translational oncology because of their reversible nature. This review provides a comprehensive summary of alterations of the epigenome in head and neck squamous cell carcinoma (HNSCC) with a focus on the methylome (hypomethylation and hypermethylation) and its predictive value in the evaluation of pathologic states and clinical outcome, or monitoring response rates to certain therapies.
| S-EPMC4905189 | biostudies-other
Project description:The immune response within the tumor microenvironment plays a key role in tumorigenesis and determines the clinical outcomes of head and neck squamous cell carcinoma (HNSCC). However, to date, a paucity of robust, reliable immune-related biomarkers has been identified that are capable of estimating prognosis in HNSCC patients. High-throughput RNA sequencing was performed in tumors and matched adjacent tissues from five HNSCC patients, and the immune signatures expression of 730 immune-related transcripts selected from the nCounter PanCancer Immune Profiling Panel were assessed. Survival analyzes were performed in a training cohort, consisting of 416 HNSCC cases, retrieved from The Cancer Genome Atlas (TCGA) database. A prognostic signature was built, using elastic net-penalized Cox regression and backward, stepwise Cox regression analyzes. The outcomes were validated by an independent cohort of 115 HNSCC patients, using tissue microarrays and immunohistochemistry staining. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was also used to estimate the relative fractions of 22 immune-cell types and their correlations coefficients with prognostic biomarkers. Collectively, 248 immune-related genes were differentially expressed in paired tumors and normal tissues using RNA sequencing. After process screening in the training TCGA cohort, four immune-related genes (PVR, TNFRSF12A, IL21R, and SOCS1) were significantly associated with overall survival (OS). Integrating these genes with Path_N stage, a multiplex model was built and suggested better performance in determining 5 years OS (receiver operating characteristic (ROC) analysis, area under the curve (AUC)=0.709) than others. Further protein-based validation was conducted in 115 HNSCC patients. Similarly, high expression of PVR and TNFRSF12A were associated with poor OS (Kaplan-Meier p=0.017 and 0.0032), while high expression of IL21R and SOCS1 indicated favorable OS (Kaplan-Meier p<0.0001 and =0.0018). The integrated model with Path_N stage still demonstrated efficacy in OS evaluation (Kaplan-Meier p<0.0001, ROC AUC=0.893). Besides, the four prognostic genes were significantly correlated with activated CD8+ T cells, CD4+ T cells, follicular helper T cells and regulatory T cells, implying the possible involvement of these genes in the immunoregulation and development of HNSCC. The well-established model encompassing both immune-related biomarkers and clinicopathological factor might serve as a promising tool for the prognostic prediction of HNSCC.
| S-EPMC7390201 | biostudies-literature
Project description:Head and neck cancer (HNC) is the fifth most common cancer worldwide. In this study, we performed an integrative analysis of the discovery set and established an eight-gene signature for the prediction of prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Univariate Cox analysis was used to identify prognosis-related genes (with P < 0.05) in the GSE41613, GSE65858, and TCGA-HNSC RNA-Seq datasets after data collection. We performed LASSO Cox regression analysis and identified eight genes (CBX3, GNA12, P4HA1, PLAU, PPL, RAB25, EPHX3, and HLF) with non-zero regression coefficients in TCGA-HNSC datasets. Survival analysis revealed that the overall survival (OS) of GSE41613 and GSE65858 datasets and the progression-free survival(DFS)of GSE27020 and GSE42743 datasets in the low-risk group exhibited better survival outcomes compared with the high-risk group. To verify that the eight-mRNA prognostic model was independent of other clinical features, KM survival analysis of the specific subtypes with different clinical characteristics was performed. Univariate and multivariate Cox regression analyses were used to identify three independent prognostic factors to construct a prognostic nomogram. Finally, the GSVA algorithm identified six pathways that were activated in the intersection of the TCGA-HNSC, GSE65858, and GSE41613 datasets, including early estrogen response, cholesterol homeostasis, oxidative phosphorylation, fatty acid metabolism, bile acid metabolism, and Kras signaling. However, the epithelial-mesenchymal transition pathway was inhibited at the intersection of the three datasets. In conclusion, the eight-gene prognostic signature proved to be a useful tool in the prognostic evaluation and facilitate personalized treatment of HNSCC patients.
| S-EPMC8252784 | biostudies-literature
Project description:Immune system dysfunction is associated with head and neck squamous cell carcinoma (HNSCC) development and progression and immune checkpoint inhibitors have demonstrated substantial survival benefits in platinum-refractory HNSCC; therefore, we examined the prognostic value of immune-related gene (IRG) expression in HNSCC. We analyzed the expression of 82 IRGs in 71 patients with HNSCC enrolled in a feasibility study for a prospective HNSCC biomarker-driven umbrella trial (Korean Cancer Study Group TRIUMPH study, NCT03292250). CD200R1 was identified as an independent prognostic factor and validated in GEO and TCGA database. CD2000R1 mRNA expression was found to be an independent favorable prognostic factor in patients with HNSCC. Moreover, CD200R1 was found to affect genes and pathways associated with the immune response, while seven differentially expressed genes (CD8A, DOK2, CX3CR1, TYROBP, CXCL9, CD300LF, IFNG) were associated with CD200R1 expression. Samples with higher CD200R1 expression displayed higher tumor-infiltrating immune cell counts both in silico and in histological analysis. These findings will help in the development of more accurate prognostic tools and suggest CD200R1 modulation as a HNSCC immunotherapy.
| S-EPMC7408128 | biostudies-literature
Project description:BackgroundThe CAV family, especially CAV1 and CAV2, is significantly associated with tumor development. In this study, we aimed to explore the pathogenic and prognostic roles of CAV1 and CAV2 in head and neck squamous cell carcinoma (HNSCC) through bioinformatic analysis and verified in human tissue.MethodsWe analyzed expression profiles of CAV1 and CAV2 in HNSCC and in normal tissues via data from The Cancer Genome Altas. Prognostic significance was examined by Kaplan-Meier survival curve obtained from the Xena browser together with Cox regression analysis. Co-expressed genes were uploaded to GeneMANIA and applied to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, showing interaction networks. Signaling pathways of CAV1 and CAV2 in HNSCC were analyzed by Gene Set Enrichment Analysis to elucidate potential regulatory mechanisms. Gene-drug interaction network was explored via Comparative Toxicogenomics Database. Immunohistochemistry was performed to verify theoretical results.ResultsCompared with normal tissues, expression levels of CAV1 and CAV2 were remarkably higher in HNSCC (p < 0.0001), which independently implies poor OS (CAV1: HR: 1.146, p = 0.027; CAV2: HR: 1.408, p = 0.002). Co-expressed genes (PXN, ITGA3, TES, and MET) were identified and analyzed by FunRich with CAV1 and CAV2, revealing a significant correlation with focal adhesion (p < 0.001), which has a vital influence on cancer progression. GSEA also showed cellular protein catabolic process (ES = 0.42) and proteasome complex (ES = 0.72), which is a key degradation system for proteins involved in oxidatively damaging and cell cycle and transcription, closely correlated with high expression of CAV2 in HNSCC. More importantly, we found the relationship between different immune cell infiltration degrees in the immune micro-environment in HNSCC and expression levels of CAV1/CAV2 (p < 0.0001). Gene-drug interaction network was checked via CTD. Moreover, tissue microarrays verified higher expression levels of CAV1/CAV2 in HNSCC (p < 0.0001), and the high expression subgroup indicated significantly poorer clinical outcomes (p < 0.05).ConclusionsThe results revealed that CAV1 and CAV2 are typically upregulated in HNSCC and might predict poor prognosis.
| S-EPMC9952890 | biostudies-literature
Project description:BACKGROUND:Advanced stage head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates. Loss-of-heterozygosity/allelic imbalance (LOH/AI) analysis has been widely used to identify genomic alterations in solid tumors and the tumor microenvironment (stroma). We hypothesize that these identified alterations can point to signaling networks functioning in HNSCC epithelial-tumor and surrounding stroma (tumor microenvironment). RESULTS:Under the assumption that genes in proximity to identified LOH/AI regions are correlated with the tumorigenic phenotype, we mined publicly available biological information to identify pathway segments (signaling proteins connected to each other in a network) and identify the role of tumor microenvironment in HNSCC. Across both neoplastic epithelial cells and the surrounding stromal cells, genetic alterations in HNSCC were successfully identified, and 75 markers were observed to have significantly different LOH/AI frequencies in these compartments (p < 0.026). We applied a network identification approach to the genes in proximity to these 75 markers in cancer epithelium and stroma in order to identify biological networks that can describe functional associations amongst these marker-associated genes. CONCLUSIONS:We verified the involvement of T-cell receptor signaling pathways in HNSCC as well as associated oncogenes such as LCK and PLCB1, and tumor suppressors such as STAT5A, PTPN6, PARK2. We identified expression levels of genes within significant LOH/AI regions specific to stroma networks that correlate with better outcome in radiation therapy. By integrating various levels of high-throughput data, we were able to precisely focus on specific proteins and genes that are germane to HNSCC.
| S-EPMC3170587 | biostudies-literature
Project description:BackgroundMetastasis is a major event for survival and prognosis in patients with head and neck squamous cell carcinomas (HNSCC). A primary cause of metastasis is the proteolytic degradation of the extracellular matrix (ECM). The plasminogen activator urokinase (PLAU) is involved in the transformation of plasminogen to plasmin leading to hydrolyzation of ECM-related proteins. However, the role of PLAU expression in HNSCC is unclear and the worth being investigated.MethodsPLAU expression profiles and clinical parameters from multiple HNSCC datasets were used to investigate the relationship of PLAU expression and HNSCC survival. GO and PPI network were established on PLAU-related downstream molecular. The stroma score was deconvoluted for analysis of PLAU's association with the immune environment. ROC analysis was applied to show the performance of PLAU in predicting HNSCC prognosis.ResultsPLAU mRNA was significantly elevated, as opposed to its methylation, in HNSCC tumor samples over normal specimens (all p < 0.01). Univariate and multivariate cox analysis showed PLAU could be an independent indicator for HNSCC prognosis. Combining with neck lymph node status, the AUC of PLAU in predicting 5-years overall survival reached to 0.862. GO enrichment analysis showed the major biological process (extracellular matrix organization and the P13K-Akt signaling pathway) may involve to the possible mechanism of PLAU's function on HNSCC prognosis. Furthermore, PLAU expression was positively correlated with stroma cell score, M1 type macrophages, and negatively associated with CD4 + T cell, Tregs cell, and follicular helper T cell.ConclusionsPLAU might be an independent biomarker for predicting outcomes of HNSCC patients. The elevated expression of PLAU was associated with HPV positivity and neck node status. The PI3K-Akt pathway and aberrant proportions of immune cells might underly the mechanism of PLAU's oncogene role in HNSCC.
| S-EPMC7812932 | biostudies-literature
Project description:The MET pathway plays a key role in various cancers, and its inhibition represents a potential treatment target. However, appropriate biomarkers are needed to facilitate the selection of patients who would benefit from MET inhibiting therapy. We herein conducted a robust confirmatory evaluation of the MET copy number alteration status and prognostic significance of c-Met expression in a large series of patients (n = 396) who underwent standard surgical resection and adjuvant chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC). Surgically resected HNSCC samples were subjected to immunohistochemical and H-score analysis of c-Met expression and silver in situ hybridization analysis of MET amplification and copy number gains. c-Met expression varied, with mean and median H-scores (scale: 0-300 scale) of 61.2 and 60.0, respectively. The lowest and highest expression levels were observed in SCC of the larynx and oral cavity, respectively. MET copy number gains were observed in 16.9% of cases (67/339) and were associated with c-Met protein expression. High c-Met expression, determined according to MET gain status, was associated with an inferior overall survival rate, especially among completely resected cases. In conclusion, our robust analysis revealed that c-Met expression in HNSCCs varied according to anatomical site, correlated with MET copy number gains, and was associated with poor prognosis. This c-Met expression analysis method, which is based on the MET gain status, appears to appropriately predict high-risk HNSCC patients in the context of anti-MET therapeutic decisions.
| S-EPMC5166528 | biostudies-literature
Project description:Glycolysis markers including glucose transporter 1 (GLUT1), monocarboxylate transporter 4 (MCT4), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2) and glucose transporter 4 (GLUT4) play vital roles in head and neck squamous cell carcinoma (HNSCC). However, their prognostic value in HNSCC is still controversial. In this meta-analysis, we searched the PubMed, Web of Science and Cochrane Library databases and included thirty-seven studies (3272 patients) that met the inclusion criteria. Higher expression levels of the glycolysis markers in tumor tissues correlated with poorer overall survival (OS; P < 0.001), disease-free survival (DFS; P = 0.03) and recurrence-free survival (RFS; P < 0.001) of HNSCC patients. Subgroup and sensitivity analyses demonstrated that higher expression levels of GLUT1 (P < 0.001), MCT4 (P = 0.002), HK2 (P = 0.002) and PKM2 (P < 0.001) correlated with poorer OS among HNSCC patients. Higher expression of MCT4 (P < 0.001) and PKM2 (P = 0.008) predicted poorer DFS among HNSCC patients. However, GLUT4 expression levels did not associate with clinical outcomes in HNSCC patients. These results demonstrate that glycolysis markers, such as GLUT1, MCT4, HK2 and PKM2, are potential prognostic predictors and therapeutic targets in HNSCC.
| S-EPMC7993722 | biostudies-literature