Dataset Information

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma.

ABSTRACT: Human papillomavirus type 16 (HPV16) is the major cause of cervical cancer and of a fraction of oropharyngeal carcinoma. Few studies compared the viral expression profiles in the two types of tumor. We analyzed HPV genotypes and viral load as well as early (E2/E4, E5, E6, E6*I, E6*II, E7) and late (L1 and L2) gene expression of HPV16 in cervical and oropharyngeal cancer biopsies. The study included 28 cervical squamous cell carcinoma (SCC) and ten oropharyngeal SCC, along with pair-matched non-tumor tissues, as well as four oropharynx dysplastic tissues and 112 cervical intraepithelial neoplasia biopsies. Viral load was found higher in cervical SCC (<1 to 694 copies/cell) and CIN (<1 to 43 copies/cell) compared to oropharyngeal SCC (<1 to 4 copies/cell). HPV16 E2/E4 and E5 as well as L1 and L2 mRNA levels were low in cervical SCC and CIN and undetectable in oropharynx cases. The HPV16 E6 and E7 mRNAs were consistently high in cervical SCC and low in oropharyngeal SCC. The analysis of HPV16 E6 mRNA expression pattern showed statistically significant higher levels of E6*I versus E6*II isoform in cervical SCC (p = 0.002) and a slightly higher expression of E6*I versus E6*II in oropharyngeal cases. In conclusion, the HPV16 E5, E6, E6*I, E6*II and E7 mRNA levels were more abundant in cervical SCC compared to oropharyngeal SCC suggesting different carcinogenic mechanisms in the two types of HPV-related cancers.

SUBMITTER: Cerasuolo A

PROVIDER: S-EPMC5470952 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma.

Cerasuolo Andrea A Annunziata Clorinda C Tortora Marianna M Starita Noemy N Stellato Giovanni G Greggi Stefano S Maglione Maria Grazia MG Ionna Franco F Losito Simona S Botti Gerardo G Buonaguro Luigi L Buonaguro Franco M FM Tornesello Maria Lina ML

Oncotarget 20170501 21

Human papillomavirus type 16 (HPV16) is the major cause of cervical cancer and of a fraction of oropharyngeal carcinoma. Few studies compared the viral expression profiles in the two types of tumor. We analyzed HPV genotypes and viral load as well as early (E2/E4, E5, E6, E6*I, E6*II, E7) and late (L1 and L2) gene expression of HPV16 in cervical and oropharyngeal cancer biopsies. The study included 28 cervical squamous cell carcinoma (SCC) and ten oropharyngeal SCC, along with pair-matched non-t ...[more]

PMID: 28423662

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Project description:The global rise of HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) has generated considerable interest underlying its etiology and management. Despite an overall decline in head and neck malignancies, the incidence in OPSCC has by contrast sharply risen, with HPV(+) subtypes now comprising 80% of all OPSCC.1,2 Relative to HPV(-) OPSCC, HPV(+) patients are more responsive to chemoradiation and harbor a 52% risk-of-death reduction.3 Despite this distinct outcome, treatment regimens remain the same for all OPSCC subtypes (smoking-driven and virus-driven), rather than an adaptive approach to what most consider distinct diseases. The short-term effects (e.g., mucositis, odynophagia) and long-term toxicities (e.g., xerostomia, dysphagia, ototoxicity) from treatment substantially affect quality of life, and rival the impact of the cancer itself. Recently published as well as ongoing trials are actively examining deintensification approaches2,4-9, with the goal of diminishing treatment sequelae for HPV(+) subtypes. While deintensification may decrease chemoradiation-related toxicities, it nonetheless may also undertreat a meaningful percentage of HPV(+) patients who may then recur. In examining national trials, 19% of HPV(+) patients had disease progression after therapy, with a two-year survival rate of 60%.10 Current methods to ascertain HPV status involve p16 staining. However, on comparison with gold standard E6/E7 expression by qPCR, p16 harbored a 15% false positivity rate11, suggesting limited utility as a sole biomarker for deintensification. Improved molecular stratification would greatly enhance the clinician’s ability to precisely tailor treatment while minimizing the risk of jeopardizing outcomes. One approach encompasses in-depth proteomic profiling of HPV(+) OPSCC to reveal distinct protein expression profiles and delineate clinically relevant upstream pathways. In turn, these proteomic differences may distinguish higher-risk disease (cases predisposed to recurrence that may benefit from treatment intensification) from lower-risk phenotypes (cases whose treatment response is sufficiently robust to warrant deintensification). Here, two HPV(+) OPSCC cohorts stratified by treatment response are compared via a hybrid data dependent acquisition/data independent acquisition (DDA/DIA) approach via mass spectrometry. We focused on detection of low-abundance proteins to highlight proteomic signatures that can be potentially exploited for treatment stratification.

Project description:Purpose/objectives: Primary small cell esophageal carcinoma (SCEC) is a rare malignancy without an established treatment strategy. This study investigated the gene expression profile of SCEC and compared it with the expression profiles of small cell lung cancer (SCLC) and esophageal adeno/squamous carcinoma (EAC/ESCC). Materials/methods: All patients with SCEC, SCLC, and EAC/ESCC in the Surveillance, Epidemiology, and End Results (SEER) database 1973-2014 were included. Overall survival (OS) and prognostic analysis were conducted. De novo expression array analysis was performed on three pairs of frozen primary SCEC tissues and the corresponding normal samples from the institutional tissue bank using the Affymetrix HG U133 plus 2.0 Array. These data were complemented with public domain expression data sets from the Gene Expression Omnibus (GEO) repository using the same working platforms, which included primary SCLC, EAC/ESCC, and normal lung/esophagus specimens (series GSE30219 and GSE26886). After individual normalization, the primary tumors were submitted to statistical analysis (GeneSpring GX 13.0) to identify the differentially expressed genes (DEGs) relative to their paired normal tissues. Enrichments of genes categorized by function and gene interactions were analyzed by DAVID 6.8 and STRING 11.0, respectively. Results: The clinical outcomes of the patients with SCEC were significantly more worse than those with EAC/ESCC and SCLC in the SEER database. SCEC had more DEGs in common with SCLC than EAC/ESCC [829 vs. 450; false discovery rate (FDR) < 0.01; and fold change ≥2], leading to a stronger correlation between SCEC and SCLC (Pearson's correlation coefficient was 0.60 for SCEC vs. SCLC, 0.51 or 0.45 for SCEC vs. ESCC or EAC, and the coefficient was 0.73 for ESCC vs. EAC). Similar findings were obtained by principal component analysis (PCA) using all DEGs retrieved from these four groups. Functional annotation showed that a higher proportion of pathways and biological processes were common between SCEC and SCLC and were associated with the cell cycle (mitosis), DNA replication, telomere maintenance, DNA repair, and P53 and RB pathways (Benjamini p < 0.05). Compared with EAC/ESCC, SCEC shared more co-upregulated DEGs coding for the aforementioned common pathways with SCLC (584 vs. 155). In addition, SCEC and SCLC were found to have possessed overlapping gene-interactive networks, with centromere protein F (CENPF), never in mitosis gene A-related kinase 2 ( NEK2), kinesin family member 11 (KIF11), thymopoietin (TMPO), and forkhead box protein M1 (FOXM1) as common skeletons centered by gene regulatory network (NUF2). Conclusions: This study is the first attempt to examine the genomic signatures of SCEC at the transcriptomic level and compare the expression profiles between SCEC, SCLC, and EAC/ESCC. Our preliminary data indicate that SCEC and SCLC display notably similar patterns of gene expression for mitosis and DNA repair. Further validation studies are warranted.

Project description:Cervical carcinoma is a global public health burden. Given that it is usually asymptomatic at potentially curative stages, the development of clinically accurate tests is critical for early detection and individual risk stratification. The present study performed an integrative meta-analysis of the transcriptomes from 10 cervical carcinoma cohorts, with the aim of identifying biomarkers that are associated with malignant transformation of cervical epithelium, and establish their clinical applicability. From among the top ranked differentially expressed genes, flap structure-specific endonuclease 1 (FEN1) and poly (U)-specific endoribonuclease (ENDOU) were selected for further validation, and their clinical applicability was assessed using immunohistochemically stained microarrays comprising 110 tissue cores, using p16 and Ki67 staining as the comparator tests. The results demonstrated that FEN1 expression was significantly upregulated in 65% of tumor specimens (P=0.0001), with no detectable expression in the non-tumor tissues. Furthermore, its expression was significantly associated with Ki67 staining in tumor samples (P<0.0001), but no association was observed with p16 expression or the presence of human papilloma virus types 16/18, patient age, tumor grade or stage. FEN1 staining demonstrated lower sensitivity than p16 (69.3 vs. 96.8%) and Ki67 (69.3 vs. 76.3%); however, the specificity was identical to p16 and higher than that of Ki67 (100 vs. 71.4%).ENDOU staining was consistent with the microarray results, demonstrating 1% positivity in tumors and 40% positivity in non-tumor tissues. Gene set enrichment analysis of cervical tumors overexpressing FEN1 revealed its association with enhanced growth factor signaling, immune response inhibition and extracellular matrix remodeling, whereas tumors with low ENDOU expression exhibited inhibition of epithelial development and differentiation processes. Taken together, the results of the present study demonstrate the feasibility of the integrative meta-analysis approach to identify relevant biomarkers associated with cervical carcinogenesis. Thus, FEN1 and ENDOU may be useful diagnostic biomarkers for squamous cervical carcinoma. However, further studies are required to determine their diagnostic performance in larger patient cohorts and validate the results presented here.

Dataset Information

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma.

Publications

Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma.

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