Dataset Information

Association between FAT1 mutation and overall survival in patients with human papillomavirus-negative head and neck squamous cell carcinoma.

ABSTRACT:

Background

The purpose of this study was to characterize the mutation profile of FAT atypical cadherin 1 (FAT1) and determine the prognostic significance of FAT1 mutation for overall survival in patients with human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).

Methods

Data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) data portals and used as discovery and validation sets. FAT1 mutational status was determined in 234 and 37 patients with HPV-negative HNSCC, respectively, and overall survival analysis was performed. For comparison, HPV-positive patients were also analyzed for overall survival.

Results

Most of the identified nonsynonymous somatic FAT1 mutations were loss-of-function mutations. FAT1 mutation was significantly associated with better overall survival in HPV-negative patients from both the TCGA cohort (p = .026) and the ICGC cohort (p = .047), but not in HPV-positive patients.

Conclusion

FAT1 mutational status is a strong independent prognostic factor in patients with HPV-negative HNSCC. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E2021-E2029, 2016.

SUBMITTER: Kim KT

PROVIDER: S-EPMC5067633 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association between FAT1 mutation and overall survival in patients with human papillomavirus-negative head and neck squamous cell carcinoma.

Kim Ki Tae KT Kim Bo-Sung BS Kim Ju Han JH

Head & neck 20160215

<h4>Background</h4>The purpose of this study was to characterize the mutation profile of FAT atypical cadherin 1 (FAT1) and determine the prognostic significance of FAT1 mutation for overall survival in patients with human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).<h4>Methods</h4>Data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) data portals and used as discovery and validation sets. FAT1 mutational status ...[more]

PMID: 26876381

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Project description:ImportanceData are limited on the prognostic value of human papillomavirus (HPV) status for head and neck carcinoma subsites.ObjectiveTo determine whether HPV positivity at each head and neck subsite is associated with improved overall survival.Design, setting, and participantsThis retrospective population-based cohort study used the National Cancer Database to identify patients diagnosed with head and neck squamous cell carcinomas from January 1, 2010, to December 31, 2014. Patients were classified according to the location of their primary malignancy into 1 of the 6 main subsites of the upper aerodigestive tract: oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, and sinonasal tract. Patients were also classified by their HPV status. Data collection for this study took place from January 1, 2010, to December 31, 2014. Data analysis was conducted from August 1, 2017, to September 30, 2017.Main outcomes and measuresThe difference in 5-year overall survival between patients with HPV-positive status and those with HPV-negative status in various head and neck carcinoma subsites; the role of HPV status in an unadjusted Cox multivariate regression model.ResultsOf the 175 223 total number of patients identified (129 634 [74.0%] male; 45 589 [26.0%] female; mean [SD] age, 63.1 [11.9] years), 133 273 (76.1%) were ineligible and 41 950 (23.9%) were included in the sample. This sample included 16 644 patients (39.7%) with HPV-positive tumors and 25 306 (60.3%) with HPV-negative tumors. Patients with an HPV-positive status were more likely to be younger, be white, be male, present with local T category tumors, and have poor differentiation on histologic examination. HPV-positive status was associated with survival at 4 tumor subsites: oral cavity (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87), oropharynx (HR, 0.44; 95% CI, 0.41-0.47), hypopharynx (HR, 0.59; 95% CI, 0.45-0.77), and larynx (HR, 0.71; 95% CI, 0.59-0.85). The HPV status was the greatest factor in survival outcome between the HPV-positive and -negative cohorts at the oropharynx subsite (77.6% vs 50.7%; survival difference, 26.9%; 95% CI, 25.6%-28.2%) and hypopharynx subsites (52.2% vs 28.8%; survival difference, 23.4%; 95% CI, 17.5%-29.3%). For the nasopharynx (HR, 1.03; 95% CI, 0.75-1.42) and sinonasal tract (HR, 0.63; 95% CI, 0.39-1.01) subsites, HPV-positive status was not an independent prognostic factor.Conclusions and relevanceHuman papillomavirus positivity was associated with improved survival in 4 subsites (oropharynx, hypopharynx, oral cavity, and larynx), and the largest survival difference was noted in the oropharynx and hypopharynx subsites. In the nasopharynx and sinonasal tract subsites, HPV positivity had no association with overall survival. Given these results, routine testing for HPV at the oropharynx, hypopharynx, oral cavity, and larynx subsites may be warranted.

Project description:For TP53-mutated head and neck squamous cell carcinomas (HNSCCs), the codon and specific amino acid sequence change resulting from a patient's mutation can be prognostic. Thus, developing a framework to predict patient survival for specific mutations in TP53 would be valuable. There are many bioinformatics and functional methods for predicting the phenotypic impact of genetic variation, but their overall clinical value remains unclear. Here, we assess the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation, using TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence. These methods include: server-based computational tools SIFT, PolyPhen-2, and Align-GVGD; our in-house POSE and VEST algorithms; the rules devised in Poeta et al. with and without considerations for splice-site mutations; location of mutation in the DNA-bound TP53 protein structure; and a functional assay measuring WAF1 transactivation in TP53-mutated yeast. We assessed method performance using overall survival (OS) and progression-free survival (PFS) from 420 HNSCC patients, of whom 224 had TP53 mutations. Each mutation was categorized as "disruptive" or "non-disruptive". For each method, we compared the outcome between the disruptive group vs. the non-disruptive group. The rules devised by Poeta et al. with or without our splice-site modification were observed to be superior to others. While the differences in OS (disruptive vs. non-disruptive) appear to be marginally significant (Poeta rules + splice rules, P = 0.089; Poeta rules, P = 0.053), both algorithms identified the disruptive group as having significantly worse PFS outcome (Poeta rules + splice rules, P = 0.011; Poeta rules, P = 0.027). In general, prognostic performance was low among assessed methods. Further studies are required to develop and validate methods that can predict functional and clinical significance of TP53 mutations in HNSCC patients.

Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common malignancy that emanates from the lips, mouth, paranasal sinuses, oropharynx, larynx, nasopharynx, and from other pharyngeal cancers. The availability of high-throughput expression data has made it possible to use global gene expression data to analyze the relationship between metabolic-related gene expression and clinical outcomes in HNSCC patients.MethodIn this study, we used RNA sequencing (RNA-seq) data from the cancer genome atlas (TCGA), with validation in the GEO dataset to profile the metabolic microenvironment and define potential biomarkers for metabolic therapy.ResultsWe extracted data for 529 patients and 327 metabolic genes (198 upregulated and 129 downregulated genes) in the TCGA database. Carbonic anhydrase 9 (CA9) and CA6 had the largest logFCs in the upregulated and downregulated genes, respectively. Our Cox regression model data showed 51 prognostic-related genes with lysocardiolipin acyltransferase 1 (LCLAT1) and choline dehydrogenase (CHDH) being associated with the highest risk (HR = 1.144, 95% CI = 1.044 ~ 1.251) and the lowest risk (HR = 0.580, 95% CI = 0.400 ~ 0.839) in HNSCC, respectively. We next used the ROC curve to evaluate whether the differentially expressed metabolic-related genes could serve as early predictors of HNSCC. The findings showed an AUC of 0.745 and 0.618 in the TCGA and GEO analysis, respectively. Besides, the ability for the genes to predict clinicopathological HNSCC status was analyzed and the data showed that the AUC for age, gender, grade, stage, T, M, and N was 0.520, 0.495, 0.568, 0.606, 0.577, 0.476, and 0.673, respectively, in the TCGA dataset. On the other hand, the AUC for age, gender, stage, T, M, N, smoking, and HPV16-pos was 0.599, 0.531, 0.622, 0.606, 0.616, 0.550, 0.614, 0.519, and 0.397, respectively, in the GEO dataset.ConclusionTaken together, our study unearths a novel metabolic gene signature for the prediction of HNSCC prognosis based on the TCGA dataset. Our signature might point out the metabolic microenvironment disorders and provides potential treatment targets and prognostic biomarkers.

Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC.MethodsMethylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients.ResultsWe initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression.ConclusionsWe established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.

Dataset Information

Association between FAT1 mutation and overall survival in patients with human papillomavirus-negative head and neck squamous cell carcinoma.

Background

Methods

Results

Conclusion

Publications

Association between FAT1 mutation and overall survival in patients with human papillomavirus-negative head and neck squamous cell carcinoma.

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