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Sharma P, Gautam SD, Rajendra S. Importance of investigating high-risk human papillomavirus in lymph node metastasis of esophageal adenocarcinoma. World J Gastroenterol 2020; 26:2729-2739. [PMID: 32550750 PMCID: PMC7284187 DOI: 10.3748/wjg.v26.i21.2729] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/18/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
High-risk human papillomavirus has been suggested as a risk factor for esophageal adenocarcinoma. Tumor human papillomavirus status has been reported to confer a favorable prognosis in esophageal adenocarcinoma. The size of the primary tumor and degree of lymphatic spread determines the prognosis of esophageal carcinomas. Lymph node status has been found to be a predictor of recurrent disease as well as 5-year survival in esophageal malignancies. In human papillomavirus driven cancers, e.g. cervical, anogenital, head and neck cancers, associated lymph nodes with a high viral load suggest metastatic lymph node involvement. Thus, human papillomavirus could potentially be useful as a marker of micro-metastases. To date, there have been no reported studies regarding human papillomavirus involvement in lymph nodes of metastatic esophageal adenocarcinoma. This review highlights the importance of investigating human papillomavirus in lymph node metastasis of esophageal adenocarcinoma based on data derived from other human papillomavirus driven cancers.
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Affiliation(s)
- Preeti Sharma
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
| | - Shweta Dutta Gautam
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
| | - Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales 2200, Australia
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Lu Y, Xu X, Nong XH, Yao DS. Detection of high-risk human papillomavirus DNA in sentinel lymph nodes of patients with cervical cancer. Oncol Lett 2020; 19:2317-2325. [PMID: 32194731 PMCID: PMC7039119 DOI: 10.3892/ol.2020.11337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 10/25/2019] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the expression of human papillomavirus (HPV) DNA in sentinel lymph nodes (SLN) in patients with early-stage cervical cancer (CC). In addition, the present study compared the positive rate of SLNs metastasis detected by routine pathological examination, and investigated the value of HPV-DNA in the detection of early CC lymph node micrometastasis. Reverse transcription-quantitative PCR (RT-qPCR) was used in order to evaluate the HPV DNA detection in all CC samples [International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IIA2]. The consistency of HPV-DNA was compared between primary lesions and SLNs. The positive rates of HPV-DNA were compared with pathological diagnosis of SLN metastasis, and the association between the positive expression of HPV-DNA in SLNs and the clinical and pathological parameters of patients with cervical cancer were analyzed. A total of 345 sentinel lymph nodes were detected in 100 patients with IA2-IIA2 CC. The positive rates of RT-qPCR and conventional histopathological detection of SLNs metastasis were 31.6% (109/345) and 12.8% (44/345), respectively (P<0.001). The positive expression of HPV-DNA in SLNs was associated with the clinical stage and tumor diameter (P<0.05), but not with patients' age, depth of cervical invasion, histological grade, lymphatic and vascular space invasion (LVSI), squamous cell carcinoma antigen (SCCAg) (P>0.05). The detection of HPV-DNA expression in pelvic lymph nodes of early CC may be used to improve the detection rate of micrometastasis, guide the postoperative adjuvant therapy more accurately and improve prognosis. Patients with positive HPV-DNA would require closer surveillance than those with negative HPV-DNA.
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Affiliation(s)
- Yan Lu
- Department of Gynecological Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - Xun Xu
- Department of Gynecological Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - Xiu-Hong Nong
- Department of Gynecological Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
| | - De-Sheng Yao
- Department of Gynecological Oncology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
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Chen P, Zhang W, Yang D, Zhang W, Gao S. Human Papillomavirus Status in Primary Lesions and Pelvic Lymph Nodes and Its Prognostic Value in Cervical Cancer Patients with Lymph Node Metastases. Med Sci Monit 2019; 25:1894-1902. [PMID: 30864560 PMCID: PMC6427929 DOI: 10.12659/msm.914564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background The aim of this study was to assess the presence of HPV DNA in cervical tissues and lymph nodes in patients who have uterine cervical neoplasms with lymphatic metastases and who underwent surgery for invasive cervical cancer and pelvic lymphadenectomy, to establish the utility of HPV type and viral load in predicting disease progression. Material/Methods We retrospectively assessed 88 patients with uterine cervical neoplasms with lymph node metastases. All 88 patients were in FIGO stage IA-IIB. A total of 316 paraffin-embedded archival tissues (88 cervical samples and 228 pelvic lymph node specimens) were acquired. All the samples were analyzed using real-time PCR to determine HPV DNA presence/type and to quantify viral load. Results In total, 17 HPV genotypes were detected in the cervical lesions and pelvic lymph nodes of the patients. The most common HPV type in all samples was HPV16, followed by HPV18. The existence of HPV16 DNA and low HPV16 viral load in cervical lesions were also significantly associated with disease recurrence. Furthermore, lymphovascular space involvement was also correlated with worse disease outcome. Conclusions HPV16 DNA presence and low viral load in primary lesions can be used to predict disease recurrence. HPV DNA is a favorable prognostic indicator in patients with uterine cervical neoplasms who have lymphatic metastases.
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Affiliation(s)
- Peng Chen
- Department of Obstetrics and Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China (mainland)
| | - Weiyuan Zhang
- Department of Obstetrics and Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China (mainland)
| | - Dong Yang
- Department of Obstetrics and Gynecology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China (mainland)
| | - Weiyang Zhang
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China (mainland)
| | - Si Gao
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin, China (mainland)
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Huang Y, He Q, Xu K, Zhou J, Yin J, Li F, Feng M, Lang J. A new marker based on risk stratification of human papillomavirus DNA and tumor size to predict survival of locally advanced cervical cancer. Int J Gynecol Cancer 2019; 29:459-465. [PMID: 30733276 DOI: 10.1136/ijgc-2018-000095] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/29/2018] [Accepted: 12/07/2018] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To assess the prognostic value of human papillomavirus (HPV) viral load in locally advanced cervical carcinoma treated with radical concurrent chemoradiotherapy. METHODS From January 2012 to October 2013, a total of 246 locally advanced cervical carcinoma patients were included in this retrospective study. HPV DNA status was tested by Hybrid Capture 2 assay. Tumor size was measured on T2WI. All the patients in the study received concurrent cisplatin-based chemoradiotherapy with intensity-modulated radiotherapy and three-dimensional brachytherapy. Survival rate was calculated by the Kaplan-Meier method, and a log-rank test was used to compare the survival. Multivariate analysis employed the Cox regression model. RESULTS The median follow-up time was 52 months. The median value of HPV DNA was 163.13 relative light unit/cut-off (RLU/CO) (range 1.65-2162.62 RLU/CO). The 5-year overall survival, distant metastasis-free survival of patients in the low HPV DNA group (HPV DNA ≤ 163.13 RLU/CO) and the high HPV DNA group (HPV DNA > 163.13 RLU/CO) were 46.3 % vs 58.5 % (p = 0.009) and 65.9 % vs 75.6% (p = 0.003), respectively. Multivariate analysis showed that the HPV DNA, tumor size, and International Federation of Gynecology and Obstetrics (FIGO) stage were independent prognostic factors for overall survival and distant metastasis-free survival. We choose the tumor size and HPV DNA as the risk stratification factors to build a new prediction marker which can better predict overall survival for locally advanced cervical cancer than can the FIGO stage. CONCLUSIONS HPV DNA may be a useful biomarker for locally advanced cervical cancer. Low HPV load predicts a worse survival. The new marker based on risk stratification by combining HPV DNA and tumor size is better associated with overall survival of locally advanced cervical cancer treated with concurrent chemoradiotherapy.
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Affiliation(s)
- Yecai Huang
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qiao He
- Department of Clinical Laboratory, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ke Xu
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jie Zhou
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jun Yin
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Fang Li
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Mei Feng
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinyi Lang
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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Annunziata C, Pezzuto F, Greggi S, Ionna F, Losito S, Botti G, Buonaguro L, Buonaguro FM, Tornesello ML. Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma. Int J Cancer 2018; 143:1153-1161. [PMID: 29603728 DOI: 10.1002/ijc.31412] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 03/20/2018] [Accepted: 03/23/2018] [Indexed: 12/18/2022]
Abstract
Two recurrent mutations (-124 G > A and -146 G > A) in the core promoter region of the human telomerase reverse transcriptase (TERT) gene create consensus binding sites for ETS transcription factors and cause increased TERT expression in several tumour types. We analyzed TERT promoter mutations and TERT mRNA levels in head and neck cancer, cervical carcinoma and cervical intraepithelial neoplasia (CIN) as well as in C-4I, CaSki, HeLa and SiHa cervical cell lines. Nucleotide sequence analysis of TERT promoter region showed that 33.3% of oral squamous cell carcinoma (SCC) and 16.8% of cervical SCC harboured mutually exclusive G to A transitions at nucleotide position -124 or -146. TERT promoter was mutated at nucleotide -146 (G > A) in SiHa cell line. Other nucleotide changes creating in some cases putative ETS binding sites were more frequent in oral SCC (26.7%) than in cervical carcinoma (4.8%). The frequency of mutations was independent of human papillomavirus (HPV) tumour status in both cervical and oral cancer. Expression of TERT gene was significantly higher in TERT promoter mutated (-124G > A or -146G > A) cervical SCC compared to not mutated SCC irrespective of HPV16 E6 and E7 levels. Such hot spot changes were not detected in oropharyngeal SCC, cervical adenocarcinoma and CIN lesions. Our results suggest that TERT promoter mutations play a relevant role in oral SCC as well as in cervical SCC, besides the already known effect of HPV16 E6 protein on TERT expression.
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Affiliation(s)
- Clorinda Annunziata
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Francesca Pezzuto
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Stefano Greggi
- Gynecology Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Franco Ionna
- Maxillofacial and Ear Nose and Throat Surgery Department, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Simona Losito
- Department of Pathology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Gerardo Botti
- Department of Pathology, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Luigi Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Franco M Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Napoli, 80131, Italy
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Cerasuolo A, Annunziata C, Tortora M, Starita N, Stellato G, Greggi S, Maglione MG, Ionna F, Losito S, Botti G, Buonaguro L, Buonaguro FM, Tornesello ML. Comparative analysis of HPV16 gene expression profiles in cervical and in oropharyngeal squamous cell carcinoma. Oncotarget 2017; 8:34070-34081. [PMID: 28423662 PMCID: PMC5470952 DOI: 10.18632/oncotarget.15977] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 02/28/2017] [Indexed: 12/22/2022] Open
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.
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Affiliation(s)
- Andrea Cerasuolo
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Clorinda Annunziata
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Marianna Tortora
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Noemy Starita
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Giovanni Stellato
- Gynecology Oncology Division, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Stefano Greggi
- Gynecology Oncology Division, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Maria Grazia Maglione
- Department of Maxillofacial and Ear Nose and Throat Surgery, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Franco Ionna
- Department of Maxillofacial and Ear Nose and Throat Surgery, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Simona Losito
- Department of Pathology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Gerardo Botti
- Department of Pathology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Luigi Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Franco M. Buonaguro
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Napoli, Italy
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