Comprehensive Genomic Review of TCGA Head and Neck Squamous Cell Carcinomas (HNSCC)

Abstract

The aim of this present study was to comprehensively describe somatic DNA alterations and transcriptional alterations in the last extension of the HNSCC subsets in TCGA, encompassing a total of 528 tumours. In order to achieve this goal, transcriptional analysis, functional enrichment assays, survival analysis, somatic copy number alteration analysis and somatic alteration analysis were carried out. A total of 3491 deregulated genes were found in HNSCC patients, and the functional analysis carried out determined that tissue development and cell differentiation were the most relevant signalling pathways in upregulated and downregulated genes, respectively. Somatic copy number alteration analysis showed a “top five” altered HNSCC genes: CDKN2A (deleted in 32.03% of patients), CDKN2B (deleted in 28.34% of patients), PPFIA1 (amplified in 26.02% of patients), FADD (amplified in 25.63% of patients) and ANO1 (amplified in 25.44% of patients). Somatic mutations analysis revealed TP53 mutation in 72% of the tumour samples followed by TTN (39%), FAT1 (23%) and MUC16 (19%). Another interesting result is the mutual exclusivity pattern that was discovered between the TP53 and PIK3CA mutations, and the co-occurrence of CDKN2A with the TP53 and FAT1 alterations. On analysis to relate differential expression genes and somatic copy number alterations, some genes were overexpressed and amplified, for example, FOXL2, but other deleted genes also showed overexpression, such as CDKN2A. Survival analysis revealed that overexpression of some oncogenes, such as EGFR, CDK6 or CDK4 were associated with poorer prognosis tumours. These new findings help us to develop new therapies and programs for the prevention of HNSCC.

Prognostic and Clinicopathological Significance of FADD Upregulation in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

“…It should also be noted that the two monoclonal antibodies used to detect FADD overexpression (Clone A66-2 and Clone H181) yielded statistically similar results predicting a reduction in OS ( p = 0.001 and p = 0.002, respectively). The results of our meta-analysis confirm what was previously reported by The Cancer Genome Atlas (TCGA) [ 18 ], which, through bioinformatics analysis of the datasets derived from 528 patients with HNSCC [ 21 ], FADD has been identified as one of the biomarkers with the highest prognostic capacity for survival; the results we present also support the findings reported by Perez-Sayans et al (2019) [ 19 ], who performed somatic copy number alteration bioinformatics analysis in order to comprehensively describe genomic aberrations in the last extension of the HNSCC subsets from TCGA. Among a total of 3491 deregulated genes found, FADD was identified as one of the “top 5” more frequently altered HNSCC genes ( CDKN2A, deleted in 32.03% of patients; CDKN2B, deleted in 28.34% of patients; PPFIA1, amplified in 26.02% of patients; FADD, amplified in 25.63% of patients; and ANO1, amplified in 25.44% of patients-) [ 19 ].…”

“…In addition to CCND1 /cyclin D1 and CTTN /cortactín [ 14 , 15 ], FADD has been proposed as a potential 11q13 amplicon driver (i.e., an amplified gene invariably found to be amplified and overexpressed, for which overexpression confers advantages to the host cell and contributes to the maintenance of the malignant phenotype) in human [ 16 ], larynx [ 17 ] and oral cancer [ 7 ]. Strikingly, in the last 5 years, FADD is booming, and this is due to the dataset reported by The Cancer Genome Atlas project (TCGA) [ 18 ] and subsequent massive bioinformatics analyses [ 19 , 20 , 21 ]. A comprehensive microarray data integration-based bioinformatics analysis using in silico tools (via Gene Expression Omnibus (GEO) and Array Express (EBI) public registers) identified FADD as one of the most promising biomarkers in HNSCC predicting poor prognosis [ 21 ].…”

Identification of Prognosis Associated microRNAs in HNSCC Subtypes Based on TCGA Dataset

“…A total of 528 samples were included from TCGA-HNSCC data base. Clinical data have been previously described elsewhere [ 14 ]. The majority of the samples were of race catalogued as “white” ( N = 452, 85.6%), followed by “black or African American race” ( N = 48, 9.1%).…”

“…The Cancer Genome Atlas (TCGA) is a database managed by the National Cancer Institute and the National Human Genome Research Institute that provides information about genomic, epigenomic, transcriptomic, and proteomic expression profiles of patients who have or have had different types of cancer (including HNSCC) [ 14 ]. New analyses are needed to assess the underlying molecular mechanisms altered in HNSCC.…”

Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15+ Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma

“…Some 90% of all HNCs are head and neck squamous cell carcinomas (HNSCCs) and HNSCCs are often associated with either carcinogens, such as alcohol and tobacco use, or oncogenic human papillomavirus (HPV) infection [2,3], thereby categorized as HPV(−) or HPV(+) HNSCCs. HNSCCs have been found to be diverse with a high rate of genetic heterogeneity, resulting in hyper-activation of oncogenes (e.g., PIK3CA and HRAS) and loss-of-function mutations in tumor suppressor genes (e.g., TP53, CASP8, and NOTCH1) [4,5]. Phosphoinositide 3-kinase (PI3K) is a frequently deregulated pathway in HNSCCs with a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene mutation rate of approximately 16% and gene amplification of more than 30% in tumors [6,7].…”