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Integration of human papillomavirus 16 in esophageal carcinoma samples.

ABSTRACT: BACKGROUND:Esophageal carcinoma (EC) is one of the major cancers in China. In 1982, Syrjanen first hypothesized the relationship between human papillomavirus (HPV) infection and the development of esophageal cancer. Since then, many reports in the field have supported this viewpoint. This study investigated the etiological relationship between HPV infection and the occurrence of esophageal carcinoma at Tangshan City of the Hebei province in China. METHODS:189 samples of esophageal carcinoma patients were collected. DNA and RNA were isolated from samples, HPV DNA was detected by polymerase chain reaction (PCR) using My09/11 for HPV L1, and HPV16 was determined using type-specific primer sets for HPV16 E6. The HPV16 integration site was verified by amplification of papillomavirus oncogene transcripts, and HPV16 oncogene transcript products were ligated to the pMD-18 T vector and sequenced to confirm the physical location of HPV16 integration. RESULTS:168 HPV-positive samples were detected in 189 samples, and among them 76 specimens were HPV16 positive. Approximately 600 bp of the HPV16 oncogene transcript were detected in nine esophageal cancer samples. Sequence analysis revealed that HPV16 E7 integrated into human chromosome 2 in three samples, into human chromosome 5 in one sample, into human chromosome 6 in one sample, into human chromosome 8 in two samples, and into human chromosome 17 in two samples. The results verified that the integrated HPV16 E7 in five samples harbored one mutation of viral DNA compared with the HPV16 sequence provided in GenBank (K02718). CONCLUSIONS:The high prevalence of HPV16 suggests that HPV16 may play an etiological role in the development of esophageal cancer. The integration of HPV16 into host cell chromosomes suggests that persistent HPV infection is key for esophageal epithelial cell malignant transformation and carcinogenesis.

SUBMITTER: Li S

PROVIDER: S-EPMC5640923 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Integration of human papillomavirus 16 in esophageal carcinoma samples.

Li Shuying S Shen Haie H Liu Zhanjun Z Li Ning N Yang Suxian S Zhang Ke K Li Jintao J

Infectious agents and cancer 20171013

<h4>Background</h4>Esophageal carcinoma (EC) is one of the major cancers in China. In 1982, Syrjanen first hypothesized the relationship between human papillomavirus (HPV) infection and the development of esophageal cancer. Since then, many reports in the field have supported this viewpoint. This study investigated the etiological relationship between HPV infection and the occurrence of esophageal carcinoma at Tangshan City of the Hebei province in China.<h4>Methods</h4>189 samples of esophageal ...[more]

PMID: 29046712

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Project description:Cervical cancer is caused by high-risk human papillomaviruses (HPV), in more than half of the worldwide cases by HPV16. Viral DNA integration into the host genome is a frequent mutation in cervical carcinogenesis. Because integration occurs into different genomic locations, it creates unique viral-cellular DNA junctions in every single case. This singularity complicates the precise identification of HPV integration sites enormously. We report here the development of a novel multiplex strategy for sequence determination of HPV16 DNA integration sites. It includes DNA fragmentation and adapter tagging, PCR enrichment of the HPV16 early region, Illumina next-generation sequencing, data processing, and validation of candidate integration sites by junction-PCR. This strategy was performed with 51 cervical cancer samples (47 primary tumors and 4 cell lines). Altogether 75 HPV16 integration sites (3'-junctions) were identified and assigned to the individual samples. By comparing the DNA junctions with the presence of viral oncogene fusion transcripts, 44 tumors could be classified into four groups: Tumors with one transcriptionally active HPV16 integrate (n = 12), tumors with transcribed and silent DNA junctions (n = 8), tumors carrying episomal HPV16 DNA (n = 10), and tumors with one to six DNA junctions, but without fusion transcripts (n = 14). The 3'-breakpoints of integrated HPV16 DNA show a statistically significant (p<0.05) preferential distribution within the early region segment upstream of the major splice acceptor underscoring the importance of deregulated viral oncogene expression for carcinogenesis. Half of the mapped HPV16 integration sites target cellular genes pointing to a direct influence of HPV integration on host genes (insertional mutagenesis). In summary, the multiplex strategy for HPV16 integration site determination worked very efficiently. It will open new avenues for comprehensive mapping of HPV integration sites and for the possible use of HPV integration sites as individualized biomarkers after cancer treatment of patients for the early diagnosis of residual and recurrent disease.

Project description:IMPORTANCE:Human papillomavirus-related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear. OBJECTIVE:To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival. DESIGN, SETTING, AND PARTICIPANTS:Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study. MAIN OUTCOMES AND MEASURES:Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis. RESULTS:Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92% (95% CI, 94%-100%) and 98% (95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months. CONCLUSIONS AND RELEVANCE:Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence.

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Integration of human papillomavirus 16 in esophageal carcinoma samples.

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Integration of human papillomavirus 16 in esophageal carcinoma samples.

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