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de Oliveira THA, Anderson LA, Craig SG, Coleman HG, Gheit T, McKay-Chopin S, Jamison J, McManus DT, Cardwell CR, Bingham V, Johnston BT, James JA, Kunzmann AT. Infectious agents and progression from Barrett's oesophagus to oesophageal adenocarcinoma: a nested case-control study. Br J Cancer 2025:10.1038/s41416-025-03003-7. [PMID: 40200065 DOI: 10.1038/s41416-025-03003-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/10/2025] [Accepted: 03/26/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND A causal role of high-risk HPV in oesophageal adenocarcinoma development has been hypothesised, but longitudinal evidence is limited. This study aims to investigate a potential causal role of infectious agents in the malignant progression of Barrett's oesophagus. METHODS Using a retrospective nested case-control study design, index Barrett's biopsies were retrieved for individuals within the Northern Ireland Barrett's oesophagus register who subsequently progressed to oesophageal adenocarcinoma (n = 150) and matched non-progressors (n = 298). Index Barrett's biopsies were assessed for the presence of 142 infectious agents by multiplex polymerase chain reaction using the Luminex platform. RNA in-situ hybridisation assessed persistent transcriptional activity in subsequent tissue samples, for infectious agents detected more frequently in progressors. RESULTS High-risk HPV genotypes (HPV16 and HPV18) were only identified in the index biopsies of progressors but not non-progressors (4% [5/150] versus 0% [0/298], P = 0.004), though no signs of persistence or transcriptional activity were observed in subsequent tissue. Prevalence of infections did not differ between progressors and non-progressors for any other infectious agents, including Helicobacter Pylori and Herpes. CONCLUSION Despite a higher prevalence of high-risk HPV in progressors than non-progressors, no evidence of transcriptionally active high-risk HPV was observed in subsequent samples, indicating presence in Barrett's is likely non-causal.
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Affiliation(s)
- Talita H A de Oliveira
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Antrim, United Kingdom.
| | - Lesley A Anderson
- Aberdeen Centre for Health Data Science, University of Aberdeen, Aberdeen, United Kingdom
| | - Stephanie G Craig
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Antrim, United Kingdom
| | - Helen G Coleman
- Centre for Public Health, Queen's University Belfast, Belfast, Antrim, United Kingdom
| | - Tarik Gheit
- International Agency for Research on Cancer-World Health Organization, Lyon, France
| | | | | | - Damian T McManus
- Institute of Pathology, Queen's University Belfast, Belfast, Antrim, United Kingdom
| | | | - Victoria Bingham
- Precision Medicine Centre, Queen's University Belfast, Belfast, Antrim, United Kingdom
| | - Brian T Johnston
- Belfast Health and Social Care Trust, Belfast, Antrim, United Kingdom
| | - Jacqueline A James
- Northern Ireland Biobank, Queen's University Belfast, Belfast, Antrim, United Kingdom
| | - Andrew T Kunzmann
- Centre for Public Health, Queen's University Belfast, Belfast, Antrim, United Kingdom
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2
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Jiang W, Zhang B, Xu J, Xue L, Wang L. Current status and perspectives of esophageal cancer: a comprehensive review. Cancer Commun (Lond) 2025; 45:281-331. [PMID: 39723635 PMCID: PMC11947622 DOI: 10.1002/cac2.12645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.
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Affiliation(s)
- Wei Jiang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
| | - Bo Zhang
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jiaqi Xu
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Liyan Xue
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Luhua Wang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
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3
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Chew DCH, Yim CHH, Ali RA, El‐Omar EM. Epidemiology, Microbiome, and Risk Factors Involved in Carcinogenesis of Esophagus, Gastric, and Intestine. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:2-22. [DOI: 10.1002/9781119756422.ch1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Xu Q, Dong H, Wang Z, Zhang P, Albers AE, Kaufmann AM, Zheng ZM, Qian X. Integration and viral oncogene expression of human papillomavirus type 16 in oropharyngeal squamous cell carcinoma and gastric cancer. J Med Virol 2023; 95:e28761. [PMID: 37212316 DOI: 10.1002/jmv.28761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 04/10/2023] [Accepted: 04/15/2023] [Indexed: 05/23/2023]
Abstract
Persistent high-risk human papillomavirus (HR-HPV) infections cause cervical cancer and a fraction of head and neck cancer. To investigate whether HR-HPV infection might be also involved in the development of gastric cancer (GC), we developed a platform utilizing a rolling circle amplification (RCA)-based nested L1 polymerase chain reaction with Sanger sequencing to genotype the HPV DNA in cancer tissues of 361 GC and 89 oropharyngeal squamous cell carcinomas (OPSCC). HPV transcriptional activity was determined by E6/E7 mRNA expression and a 3' rapid amplification of cDNA ends was performed to identify HPV integration and expression of virus-host fusion transcripts. Ten of 361 GC, 2 of 89 OPSCC, and 1 of 22 normal adjacent tissues were HPV L1 DNA-positive. Five of the 10 HPV-positive GC were genotyped as HPV16 by sequencing and 1 of 2 GC with RCA/nested HPV16 E6/E7 DNA detection exhibited HPV16 E6/E7 mRNA. Two OPSCC displayed HPV16 L1 DNA and E6/E7 mRNA, of which 1 OPSCC tissue showed virus-host RNA fusion transcripts from an intron region of KIAA0825 gene. Together, our data reveal viral oncogene expression and/or integration in GC and OPSCC and a possible etiology role of HPV infections in gastric carcinogenesis.
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Affiliation(s)
- Qiang Xu
- Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Haoru Dong
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Postgraduate Education Base, Wenzhou Medical University, Wenzhou, China
| | - Zhiyu Wang
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Postgraduate Education Base, Wenzhou Medical University, Wenzhou, China
| | - Pei Zhang
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Andreas E Albers
- Department of Clinical Medicine, Oto-Rhino-Laryngology, Medical School Berlin, Berlin, Germany
| | - Andreas M Kaufmann
- Clinic for Gynecology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Zhi-Ming Zheng
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA
| | - Xu Qian
- Department of Clinical Laboratory, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Postgraduate Education Base, Wenzhou Medical University, Wenzhou, China
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5
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Sofiani VH, Veisi P, Rukerd MRZ, Ghazi R, Nakhaie M. The complexity of human papilloma virus in cancers: a narrative review. Infect Agent Cancer 2023; 18:13. [PMID: 36843070 PMCID: PMC9969657 DOI: 10.1186/s13027-023-00488-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 02/09/2023] [Indexed: 02/27/2023] Open
Abstract
Among human tumorigenic viruses, the role of Human papillomavirus (HPV) has been proven as one of the most important oncoviruses that are associated with a large number of cancers. Most cancers of the genital area such cervical and anal cancer as are caused by HPV, and in many other cancers, such as colorectal, gastric, liver, esophageal, urinary bladder, and head and neck cancers, it is considered as one of the important risk factors. Our search was conducted for published researches between 2000 and 2022 by using several international databases including Scopus, PubMed, and Web of Science as well as Google scholar. We also evaluated additional evidence from relevant published articles. It has been demonstrated that HPV can promote tumorigenesis via focusing on genes, proteins, and signaling pathways, by using E6 and E7 oncoproteins and inhibiting two crucial tumor suppressors, P53 and Rb. The following study was performed to investigate different malignant cancers under the influence of HPV infection and changes in molecular factors caused by HPV infection.
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Affiliation(s)
- Vahideh Hamidi Sofiani
- grid.411747.00000 0004 0418 0096Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Parsa Veisi
- grid.411747.00000 0004 0418 0096Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Rezaei Zadeh Rukerd
- grid.412105.30000 0001 2092 9755Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Reza Ghazi
- Department of Biotechnology, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Mohsen Nakhaie
- Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
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Rajendra S, Sharma P. Causal Link of Human Papillomavirus in Barrett Esophagus and Adenocarcinoma: Are We There Yet? Cancers (Basel) 2023; 15:cancers15030873. [PMID: 36765833 PMCID: PMC9913573 DOI: 10.3390/cancers15030873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/07/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Esophageal cancer is a relatively common malignancy worldwide with a high mortality (5-year survival of <15%). Despite screening, surveillance, improved imaging and treatment, the exponential rise in OAC continues. The strongest risk factors for OAC are chronic heartburn and metaplastic transformation of the lower third of the esophagus (Barrett's esophagus). The risk profile includes Caucasian race, male gender older age, obesity and smoking. Although the tumor risk in BO has been progressively revised downwards, the exponential rise in OAC remains unchecked. This paradox points to an unidentified missing link. Relatively recently, we provided the world's initial data for a strong association of biologically relevant hr-HPV with BD and OAC. Since then, systematic reviews and meta-analysis have documented HPV DNA prevalence rates in OAC of between 13 to 35%. In this review, we provide some evidence for a probable causal relationship between hr-HPV and OAC. This is challenging given the multifactorial etiology and long latency. Increasingly, high-risk HPV (hr-HPV) is regarded as a risk factor for OAC. This discovery will aid identification of a sub-group of high-risk progressors to esophageal cancer by surveillance and the development of effective preventive strategies including vaccination.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, NSW 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW 2052, Australia
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South-Western Sydney Local Health Network, Bankstown, Sydney, NSW 2200, Australia
- Correspondence: ; Tel.: +61-(0)-2-9722-8814; Fax: +61-(0)-9722-8570
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO 64128, USA
- School of Medicine, University of Kansas, Kansas City, MO 66160, USA
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Burassakarn A, Pientong C, Tongchai P, Wongjampa W, Poosari A, Udomsin A, Sa-ngiamwibool P, Ungareewittaya P, Nutravong T, Ekalaksananan T. Epidemiological evidence and association of human papillomavirus with esophageal cancer in northeastern Thailand: a case-control study. Front Microbiol 2023; 14:1146322. [PMID: 37180234 PMCID: PMC10172481 DOI: 10.3389/fmicb.2023.1146322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/31/2023] [Indexed: 05/16/2023] Open
Abstract
Recently, epidemiological evidence of high-risk human papillomavirus (hrHPV) and its association with the increasing risk of esophageal cancer (EC) have been described. However, the involvement of such a virus in the pathogenesis of EC is still inconclusive in the literature. Therefore, our objective was to clarify the epidemiology of HPV infections in primarily diagnosed EC cases and validate this correlation with hospital-based control patients using a retrospective study with a case-control model. Here, we reported that the overall prevalence of HPV DNA was statistically associated with an increased risk of EC (OR, 3.3; 95% CI, 2.5-4.3). Interestingly, a history of gastroesophageal reflux disease (GERD) was constituted and significantly associated with HPV prevalence (adjusted OR, 4.6; 95% CI, 2.2-9.5). Furthermore, our meta-analysis in public databases also indicated that the combined OR and 95% CI between HPV infection and EC risk were 3.31 and 2.53-4.34, respectively, with significant heterogeneity (I2 = 78%). Variations in the geographic study, tissue type, and detection method remain potential predictors of heterogeneity. In addition, publication bias and sensitivity analysis were not observed, and the results exhibited stable outcomes. Collectively, we specify the recent epidemiological evidence in a validation of the distributed HPV, which might be statistically associated with an increased risk of EC. However, additional high-quality studies with larger sample sizes are needed to further verify the link between HPV and EC.
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Affiliation(s)
- Ati Burassakarn
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen, Thailand
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen, Thailand
| | - Panwad Tongchai
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen, Thailand
| | - Weerayut Wongjampa
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen, Thailand
| | - Arisara Poosari
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | | | - Piti Ungareewittaya
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Thitima Nutravong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen, Thailand
- *Correspondence: Tipaya Ekalaksananan,
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9
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Zheng Y, Niu X, Wei Q, Li Y, Li L, Zhao J. Familial Esophageal Cancer in Taihang Mountain, China: An Era of Personalized Medicine Based on Family and Population Perspective. Cell Transplant 2022; 31:9636897221129174. [PMID: 36300368 PMCID: PMC9618747 DOI: 10.1177/09636897221129174] [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] [Indexed: 11/15/2022] Open
Abstract
In the Taihang Mountain areas, known as the “esophageal cancer zone” in China, the incidence of esophageal cancer (ESCA) ranks the first in the country and shows a familial and regional clustering trend. Taihang Mountain areas are located in a mountainous area, with inconvenient transportation, limited living conditions, unbalanced diet, and poor nutrition. Ninety percent of the pathological types of ESCA in Taihang Mountain areas are squamous cell carcinoma, among which the risk factors have not been well understood. These areas are usually remote villages and mountains with low population mobility, large family members, similar environmental factors, and a clear and stable genetic background. Therefore, according to the current situation, second-generation sequencing and multigroup analysis technology are used to analyze the familial ESCA patients; disease-related genetic variation are located; and then disease-related susceptibility genes associated with ESCA are screened and analyzed. Health education, tobacco control, endoscopic screening, and other health management projects for suspected and high-risk patients in areas with a high incidence of ESCA can be carried out for screening and early diagnosis, and the incidence of ESCA in Taihang Mountain areas can be reduced. A comprehensive continuous care pattern based on traditional medical nursing to track, monitor, evaluate, and intervene with patients diagnosed with ESCA to facilitate them with medications guidance, dietary guidance, and timely health problem-solving is established. Furthermore, statistical analysis of epidemiology, gene sequencing, and family genetics information can be performed on patients with ESCA in the Taihang Mountains areas to clarify the relationship between genetic phenotype and genotype during the occurrence of ESCA.
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Affiliation(s)
- Yuanyuan Zheng
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyu Niu
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Qian Wei
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yijing Li
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lifeng Li
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Biological Cell Therapy Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Zhao
- National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,Jie Zhao, National Engineering Laboratory for Internet Medical Systems and Applications, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
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Li S, Luk HY, Xia C, Chen Z, Chan PKS, Boon SS. Oesophageal carcinoma: The prevalence of DNA tumour viruses and therapy. Tumour Virus Res 2022; 13:200231. [PMID: 34920177 PMCID: PMC8717602 DOI: 10.1016/j.tvr.2021.200231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/02/2021] [Accepted: 12/10/2021] [Indexed: 12/11/2022] Open
Abstract
Oesophageal carcinoma ranks the sixth leading cause of cancer death and affected 544,000 - 604,000 people in 2020. Patients often presented with a poor cancer prognosis with a low survival rate of 15-25%. Depending upon the cell type, oesophageal carcinoma is categorised into oesophageal squamous cell carcinoma (ESCC) and oesophageal adenocarcinoma (EAC). ESCC is predominantly reported in developing countries, while EAC is more common in developed countries. Aside from the presence of exogenous co-factors, such as cigarette smoking, alcohol consumption, obesity, gastroesophageal reflux disease (GERD); infection with oncogenic viruses is suspected to be one of the major factors contributing to EC development. Oncogenic viruses, including human papillomavirus (HPV), Epstein Barr virus (EBV), Cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) have been detected in various proportions of EC samples. Nonetheless, their aetiological roles in EC remain debatable. In this review, we garnered previous studies that focus on the association between oncogenic viruses and EC. Among these oncogenic viruses, HPV appears to have a stronger association with EC than the others. In addition, we also discuss the pros and cons of the treatment regimens to treat EC patients, including immunotherapy, chemo- and chemoradiotherapy, and their efficacy.
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Affiliation(s)
- Sile Li
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region of China
| | - Ho Yin Luk
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region of China
| | - Chichao Xia
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region of China
| | - Zigui Chen
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region of China
| | - Paul Kay Sheung Chan
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region of China
| | - Siaw Shi Boon
- Department of Microbiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong Special Administrative Region of China.
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Baj J, Forma A, Dudek I, Chilimoniuk Z, Dobosz M, Dobrzyński M, Teresiński G, Buszewicz G, Flieger J, Portincasa P. The Involvement of Human Papilloma Virus in Gastrointestinal Cancers. Cancers (Basel) 2022; 14:2607. [PMID: 35681587 PMCID: PMC9179480 DOI: 10.3390/cancers14112607] [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: 04/18/2022] [Revised: 05/21/2022] [Accepted: 05/22/2022] [Indexed: 01/27/2023] Open
Abstract
Human Papilloma Virus (HPV) is one of the most common sexually transmitted infections worldwide. HPV infection has a strong relationship with the onset of cervix uteri, vagina, penis, anus, and oropharynx, but also tonsils and tongue cancers. Some epidemiological data indicate that except for gynecologic cancers, HPV infection can be one of the risk factors associated with a greater risk of induction and progression of gastrointestinal cancers. Data, however, remain contradictory and definite conclusions cannot be drawn, so far. The following review aims to organize recent evidence and summarize the current state of knowledge regarding the association between HPV infection and gastrointestinal tumors primarily focusing on esophageal, liver, gastric, colorectal, and anal cancers.
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Affiliation(s)
- Jacek Baj
- Department of Anatomy, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland
| | - Alicja Forma
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Iga Dudek
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Zuzanna Chilimoniuk
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Maciej Dobosz
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Michał Dobrzyński
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Grzegorz Teresiński
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Grzegorz Buszewicz
- Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (I.D.); (Z.C.); (M.D.); (M.D.); (G.T.); (G.B.)
| | - Jolanta Flieger
- Department of Analytical Chemistry, Medical University of Lublin, Chodźki 4A, 20-093 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
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Rajendra K, Sharma P. Viral Pathogens in Oesophageal and Gastric Cancer. Pathogens 2022; 11:476. [PMID: 35456151 PMCID: PMC9029269 DOI: 10.3390/pathogens11040476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 04/10/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022] Open
Abstract
Tumour virology was born with the discovery by Peyton Rous in 1911 of a filterable agent in chicken cellular extracts that caused neoplasia in healthy chickens. Universally, 20% of all human cancers have a viral aetiology. Viruses are involved at various stages of the carcinogenesis pathway, depending on the viral pathogen, and likely require co-factors. Multiple risk factors have been associated with oesophageal and gastric malignancy, including carcinogenic pathogens. These viruses and bacteria include human papillomavirus (HPV) [oesophageal cancer], Epstein-Barr virus (EBV) [proximal stomach cancer], and Helicobacter pylori (HP) [non-cardia stomach cancer]. Viruses such as EBV have been firmly established as causal for up to 10% of gastric cancers. HPV is associated with 13 to 35% of oesophageal adenocarcinoma but its role is unclear in oesophageal squamous cell carcinomas. The causal relationship between hepatitis B (HBV), cytomegalovirus (CMV), HPV, and John Cunningham (JCV) and gastric neoplasia remains indeterminate and warrants further study. The expression of viral antigens by human tumours offers preventive and therapeutic potential (including vaccination) and has already been harnessed with vaccines for HPV and HBV. Future goals include viral protein-based immunotherapy and monoclonal antibodies for the treatment of some of the subset of EBV and HPV-induced gastro-esophageal cancers.
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Affiliation(s)
- Kishen Rajendra
- School of Medicine, The International Medical University, Kuala Lumpur 57000, Malaysia
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MO 64128, USA;
- School of Medicine, University of Kansas, Kansas City, MO 66160, USA
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White JR, Ragunath K, Whitton A, Marsh E, Kaye P, Knight G. Study to investigate the prevalence of human papillomavirus in Barrett's oesophagus using a novel screening methodology. BMJ Open Gastroenterol 2022; 9:bmjgast-2021-000840. [PMID: 35379652 PMCID: PMC8981274 DOI: 10.1136/bmjgast-2021-000840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/25/2022] [Indexed: 11/30/2022] Open
Abstract
Introduction Human papillomavirus (HPV) is strongly associated with Barrett’s dysplasia and oesophageal cancer suggesting a role in carcinogenesis. HPV persistence predicts treatment failure after endotherapy for Barrett’s dysplasia. This pilot study applies a novel HPV screening tool (previously only used in the oropharynx) to detect HPV DNA directly and determine the prevalence rates in Barrett’s oesophagus (BO). Method DNA was extracted from 20 formalin-fixed BO samples. HPV DNA was detected using real-time PCR and gel electrophoresis. Results 5 out of 20 patients were identified as positive for HPV. Prevalence was 25% in patients with BO. Conclusion This method can be used in BO’s tissue to determine HPV infection. Adoption of this as a screening test could potentially revolutionise future research in this area. If a clear link between HPV and Barrett’s dysplasia can be confirmed, this qPCR method has the potential to aid in monitoring and/or dysplasia detection by stratifying those most at risk and aid in the development of new therapies.
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Affiliation(s)
- Jonathan Richard White
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Krish Ragunath
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Aimee Whitton
- School of Human Sciences, University of Derby, Derby, UK
| | | | - Philip Kaye
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Gillian Knight
- School of Engineering and Applied Science, Aston University, Birmingham, UK
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14
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Dan W, Peng L, Yan B, Li Z, Pan F. Human Microbiota in Esophageal Adenocarcinoma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Implications. Front Microbiol 2022; 12:791274. [PMID: 35126331 PMCID: PMC8815000 DOI: 10.3389/fmicb.2021.791274] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/23/2021] [Indexed: 11/29/2022] Open
Abstract
Esophageal adenocarcinoma (EAC) is one of the main subtypes of esophageal cancer. The incidence rate of EAC increased progressively while the 5-year relative survival rates were poor in the past two decades. The mechanism of EAC has been studied extensively in relation to genetic factors, but less so with respect to human microbiota. Currently, researches about the relationship between EAC and the human microbiota is a newly emerging field of study. Herein, we present the current state of knowledge linking human microbiota to esophageal adenocarcinoma and its precursor lesion—gastroesophageal reflux disease and Barrett’s esophagus. There are specific human bacterial alternations in the process of esophageal carcinogenesis. And bacterial dysbiosis plays an important role in the process of esophageal carcinogenesis via inflammation, microbial metabolism and genotoxicity. Based on the human microbiota alternation in the EAC cascade, it provides potential microbiome-based clinical application. This review is focused on novel targets in prevention, diagnosis, prognosis, and therapy for esophageal adenocarcinoma.
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Affiliation(s)
- Wanyue Dan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Nankai University, Tianjin, China
| | - Lihua Peng
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bin Yan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhengpeng Li
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Fei Pan,
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15
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Yao C, Li Y, Luo L, Xiong Q, Zhong X, Xie F, Feng P. Identification of miRNAs and genes for predicting Barrett's esophagus progressing to esophageal adenocarcinoma using miRNA-mRNA integrated analysis. PLoS One 2021; 16:e0260353. [PMID: 34818353 PMCID: PMC8612537 DOI: 10.1371/journal.pone.0260353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 11/08/2021] [Indexed: 11/29/2022] Open
Abstract
Barrett's esophagus (BE) is defined as any metaplastic columnar epithelium in the distal esophagus, which predisposes to esophageal adenocarcinoma (EAC). Yet, the mechanism through which BE develops to EAC still remain unclear. Moreover, the miRNA-mRNA regulatory network in distinguishing BE from EAC still remains poorly understood. To identify differentially expressed miRNAs (DEMs) and genes (DEGs) between EAC and BE from tissue samples, gene expression microarray datasets GSE13898, GSE26886, GSE1420 and miRNA microarray datasets GSE16456, GSE20099 were downloaded from Gene Expression Omnibus (GEO) database. GEO2R was used to screen the DEMs and DEGs. Pathway and functional enrichment analysis were performed by DAVID database. The protein-protein interaction (PPI) network was constructed by STRING and been visualized by Cytoscape software. Finnal, survival analysis was performed basing TCGA database. A total of 21 DEMs were identified. The enriched functions and pathways analysis inclued Epstein-Barr virus infection, herpesvirus infection and TRP channels. GART, TNFSF11, GTSE1, NEK2, ICAM1, PSMD12, CTNNB1, CDH1, PSEN1, IL1B, CTNND1, JAG1, CDH17, ITCH, CALM1 and ITGA6 were considered as the hub-genes. Hsa-miR-143 and hsa-miR-133b were the highest connectivity target gene. JAG1 was predicted as the largest number of target miRNAs. The expression of hsa-miR-181d, hsa-miR-185, hsa-miR-15b, hsa-miR-214 and hsa-miR-496 was significantly different between normal tissue and EAC. CDH1, GART, GTSE1, NEK2 and hsa-miR-496, hsa-miR-214, hsa-miR-15b were found to be correlated with survival.
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Affiliation(s)
- Chengjiao Yao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Geriatrics of the Affiliated Hospital, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Yilin Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
| | - Lihong Luo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qin Xiong
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaowu Zhong
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, Sichuan, China
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
- * E-mail: (PF); (XZ)
| | - Fengjiao Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Peimin Feng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- * E-mail: (PF); (XZ)
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16
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Chumduri C, Gurumurthy RK, Berger H, Dietrich O, Kumar N, Koster S, Brinkmann V, Hoffmann K, Drabkina M, Arampatzi P, Son D, Klemm U, Mollenkopf HJ, Herbst H, Mangler M, Vogel J, Saliba AE, Meyer TF. Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. Nat Cell Biol 2021; 23:184-197. [PMID: 33462395 PMCID: PMC7878191 DOI: 10.1038/s41556-020-00619-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 11/26/2020] [Indexed: 12/11/2022]
Abstract
The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.
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Affiliation(s)
- Cindrilla Chumduri
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
- Chair of Microbiology, University of Würzburg, Würzburg, Germany.
| | | | - Hilmar Berger
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Oliver Dietrich
- Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany
| | - Naveen Kumar
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
- Chair of Microbiology, University of Würzburg, Würzburg, Germany
| | - Stefanie Koster
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Volker Brinkmann
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Kirstin Hoffmann
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Marina Drabkina
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | | | - Dajung Son
- Chair of Microbiology, University of Würzburg, Würzburg, Germany
| | - Uwe Klemm
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Hans-Joachim Mollenkopf
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Hermann Herbst
- Institute of Pathology, Vivantes Klinikum Berlin, Berlin, Germany
| | - Mandy Mangler
- Department of Gynecology, Charité University Medicine, Berlin, Germany
- Klinik für Gynäkologie und Geburtsmedizin, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany
| | - Jörg Vogel
- Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany
- Institute of Molecular Infection Biology, University of Würzburg, Würzburg, Germany
| | - Antoine-Emmanuel Saliba
- Institute for RNA-based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), Würzburg, Germany
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology (IKMB), Christian Albrechts University of Kiel, Kiel, Germany.
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17
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Chang C, Worrell SG. Viruses and esophageal cancer. Dis Esophagus 2020; 33:5847897. [PMID: 32462190 DOI: 10.1093/dote/doaa036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 04/14/2020] [Accepted: 04/18/2020] [Indexed: 12/11/2022]
Abstract
Esophageal adenocarcinoma (EAC) has had the fastest increasing incidence of any solid tumor in the United States in the last 30 years. Long standing gastroesophageal reflux disease is a well-established risk factor with strong associations with obesity, alcohol and tobacco. However, there are likely additional contributing factors. Viruses such as human papillomavirus, ebstein-barr virus and herpes simplex virus have been implicated in the pathogenesis of esophageal cancer. This review will discuss the known literature linking viruses to esophageal adenocarcinoma and consider future relationships such as identifying prognostic and predictive molecular biomarkers to guide therapies.
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Affiliation(s)
- Carolyn Chang
- Case Western Reserve School of Medicine, Cleveland, OH, USA
| | - Stephanie G Worrell
- Case Western Reserve School of Medicine, Cleveland, OH, USA.,University Hospitals Cleveland Medical Center, Cleveland, OH, USA
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18
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Rajendra S, Pavey D, McKay O, Merrett N, Gautam SD. Human papillomavirus infection in esophageal squamous cell carcinoma and esophageal adenocarcinoma: a concise review. Ann N Y Acad Sci 2020; 1482:36-48. [PMID: 33103249 DOI: 10.1111/nyas.14509] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/05/2020] [Accepted: 09/17/2020] [Indexed: 12/24/2022]
Abstract
The causal link between high-risk human papillomavirus (hr-HPV) infection and cervical, anogenital, and some oropharyngeal malignancies has been established by both molecular and epidemiological data. The association between HPV and esophageal squamous cell carcinoma (ESCC) remains controversial, as is the true prevalence of HPV infection in ESCC. The wide range in reported rates reflects variability in the primary literature, with some larger scale case-control studies suggesting the infection rates range from 0% to 78%. Interactions between HPV and the Barrett's metaplasia-dysplasia-carcinoma sequence have been explored, and these studies have shown some conflicting data. Overall, systematic reviews have reported the prevalence of HPV-positive DNA in esophageal adenocarcinoma patients of between 13% and 35%. Postulated reasons for discrepancies in HPV prevalence rates in esophageal cancer include variations in testing methodology and assay sensitivities; technical issues, including the lack of a gold-standard primer; types of specimens utilized (fresh-frozen versus formalin-fixed tissue); geographical variation; cross-contamination; and small sample sizes. Thus, efforts must be undertaken to (1) standardize HPV testing, ideally in a central laboratory and utilizing tests that detect viral transcriptional activity; (2) avoid cross-contamination; and (3) recruit large numbers of patients to accurately ascertain HPV rates in esophageal malignancy.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Darren Pavey
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Owen McKay
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Neil Merrett
- Discipline of Surgery, School of Medicine, Western Sydney University, Penrith, New South Wales, Australia.,Department of Upper Gastrointestinal Surgery, Bankstown-Lidcombe Hospital, Bankstown, Sydney, New South Wales, Australia
| | - Shweta Dutta Gautam
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia
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19
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Nakhaie M, Charostad J, Kaydani GA, Faghihloo E. The role of viruses in adenocarcinoma development. INFECTION GENETICS AND EVOLUTION 2020; 86:104603. [PMID: 33091575 DOI: 10.1016/j.meegid.2020.104603] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 10/15/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2022]
Abstract
Cancer is a leading public health issue that accounts for million deaths around the world every year. Human cancers contain over 100 types, which are categorized into different groups. Adenocarcinoma is one of those categories of cancer that begins from the glans and involves various tissues such as lung, esophagus, pancreas, prostate and colorectal. A range of risk factors has been identified for the development and progression of adenocarcinomas. One of these risk factors are viruses that serves special mechanisms to affect important host cell factors and tumorigenic pathways, contributing in development and promotion of adenocarcinomas. Here, we summarized the main viruses and their mechanisms implicated in the course of various adenocarcinomas development.
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Affiliation(s)
- Mohsen Nakhaie
- Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Medical Microbiology, Kerman University of Medical Sciences, Kerman, Iran
| | - Javad Charostad
- Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Microbiology, Shahid Sadoghi University of Medical Science, Yazd, Iran
| | - Gholam Abbas Kaydani
- Department of Laboratory Sciences, Student Research Committee, School of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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20
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Gupta R, Rady PL, Sikora AG, Tyring SK. The role of human papillomavirus in the pathogenesis of sinonasal inverted papilloma: a narrative review. Rev Med Virol 2020; 31:e2178. [PMID: 33048407 DOI: 10.1002/rmv.2178] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 12/24/2022]
Abstract
Sinonasal inverted papillomas (IPs) are rare tumours arising from the nasal epithelial mucosa. Most lesions are benign, but a subset of IPs progress to dysplasia and squamous cell carcinoma. Although the epidemiology and clinical features of IPs are well known, the pathogenesis is still unclear. Given the established role of human papillomaviruses (HPVs) in the formation of other mucosal tumours including cervical and oropharyngeal cancer, some have suggested the virus may play a role in IP development. However, the association between HPV and IPs has not yet been proven, and the variable detection of HPV DNA in IPs has cast uncertainty on whether the virus plays a major role in pathogenesis. In this review, we summarize early clinical reports and synthesize recent studies that may elucidate the association between HPV and IPs. We also discuss the role HPV may have in the progression of benign IP to dysplasia and malignancy, as well as potential pathological mechanisms. We hope that synthesizing the initial and recent studies on this topic will not only lead to a better understanding of research in the role of HPV in IP development, but also help guide and contextualize future studies.
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Affiliation(s)
- Rohit Gupta
- School of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Peter L Rady
- Department of Dermatology, The University of Texas McGovern Medical School, Houston, TX, USA
| | - Andrew G Sikora
- Bobby R. Alford Department of Otolaryngology - Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Stephen K Tyring
- Department of Dermatology, The University of Texas McGovern Medical School, Houston, TX, USA
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21
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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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22
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Bouzid R, Peppelenbosch M, Buschow SI. Opportunities for Conventional and in Situ Cancer Vaccine Strategies and Combination with Immunotherapy for Gastrointestinal Cancers, A Review. Cancers (Basel) 2020; 12:cancers12051121. [PMID: 32365838 PMCID: PMC7281593 DOI: 10.3390/cancers12051121] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 12/17/2022] Open
Abstract
Survival of gastrointestinal cancer remains dismal, especially for metastasized disease. For various cancers, especially melanoma and lung cancer, immunotherapy has been proven to confer survival benefits, but results for gastrointestinal cancer have been disappointing. Hence, there is substantial interest in exploring the usefulness of adaptive immune system education with respect to anti-cancer responses though vaccination. Encouragingly, even fairly non-specific approaches to vaccination and immune system stimulation, involving for instance influenza vaccines, have shown promising results, eliciting hopes that selection of specific antigens for vaccination may prove useful for at least a subset of gastrointestinal cancers. It is widely recognized that immune recognition and initiation of responses are hampered by a lack of T cell help, or by suppressive cancer-associated factors. In this review we will discuss the hurdles that limit efficacy of conventional cancer therapeutic vaccination methods (e.g., peptide vaccines, dendritic cell vaccination). In addition, we will outline other forms of treatment (e.g., radiotherapy, chemotherapy, oncolytic viruses) that also cause the release of antigens through immunogenic tumor cell death and can thus be considered unconventional vaccination methods (i.e., in situ vaccination). Finally, we focus on the potential additive value that vaccination strategies may have for improving the effect immunotherapy. Overall, a picture will emerge that although the field has made substantial progress, successful immunotherapy through the combination with cancer antigen vaccination, including that for gastrointestinal cancers, is still in its infancy, prompting further intensification of the research effort in this respect.
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23
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Rajendra S, Xuan W, Hufnagel K, Sharma P, Pavey D, Alhajjiri N, Rattan A, Wang B. Antibodies against human papillomavirus proteins in Barrett's dysplasia and intramucosal esophageal adenocarcinoma. Ann N Y Acad Sci 2020; 1470:44-56. [PMID: 32170783 DOI: 10.1111/nyas.14328] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/10/2020] [Accepted: 02/17/2020] [Indexed: 12/18/2022]
Abstract
High-risk human papillomavirus (HPV) types 16/18 have been associated with Barrett's dysplasia (BD)/esophageal adenocarcinoma (EAC). Nevertheless, no data exist in relation to serological analysis for HPV antibodies in BD/EAC with site-specific viral DNA status. We prospectively examined antibodies to multiple HPV types in 438 patients representing hospital/reflux controls and Barrett's metaplasia (BM)/BD/intramucosal EAC. Antibody responses to HPV6/11/16/18/31/33/45/52/58 were analyzed using multiplex serology, including antibodies to E6/E7/E1/E2 and L1 antigens. Seropositivity for individual HPV proteins was infrequent in both cases and controls and was ≤10.2%. There was no difference in the seroprevalence of antibodies to any HPV antigen/antibody combination between reclassified cases (BD/EAC) and controls (hospital/reflux/BM) or between HPV16 or HPV18 DNA cases and controls, respectively. Among HPV16 DNA-positive BD/EAC cases, antibodies to HPV16 E7 were significantly more prevalent (3/26, 11.5%) than in hospital and reflux controls plus BM (5/328, 1.5%) (adjusted OR = 10.12, 95% CI: 1.61-63.73, P = 0.014). Among HPV18 DNA-positive cases, antibodies to HPV18 E1 were present in 3/6 (50%) cases versus 5/328 (1.5%) controls (adjusted OR = 44.28, 95% CI: 6.10-321.47, P = 0.0002). Although antibodies against HPV were generally uncommon in cases and controls, immune responses against two early proteins of HPV16/18 were significantly more frequent in viral DNA-positive BD/intramucosal EAC.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Wei Xuan
- South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia.,Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Katrin Hufnagel
- Infections and Cancer Epidemiology, Infection, Inflammation and Cancer Research Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas School of Medicine, Kansas City, Missouri
| | - Darren Pavey
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Noureddin Alhajjiri
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Arti Rattan
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Bin Wang
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia
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Rajendra S, Sharma P, Gautam SD, Saxena M, Kapur A, Sharma P, Merrett N, Yang T, Santos LD, Pavey D, Sharaiha O, McKay O, Dixson H, Xuan W. Association of Biomarkers for Human Papillomavirus With Survival Among Adults With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma. JAMA Netw Open 2020; 3:e1921189. [PMID: 32058552 DOI: 10.1001/jamanetworkopen.2019.21189] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
IMPORTANCE The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. OBJECTIVE To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. DESIGN, SETTING, AND PARTICIPANTS This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. MAIN OUTCOMES AND MEASURES Disease-free survival and overall survival. RESULTS Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjusted P = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjusted P = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P = .04). CONCLUSIONS AND RELEVANCE This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
- Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Preeti Sharma
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
| | - Shweta Dutta Gautam
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
| | - Manoj Saxena
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
- Department of Intensive Care, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Amit Kapur
- Graduate School of Medicine, The University of Wollongong, Wollongong, New South Wales, Australia
| | - Prateek Sharma
- Veterans Affairs Medical Center, Division of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Missouri
| | - Neil Merrett
- Discipline of Surgery, Western Sydney University School of Medicine, Penrith, New South Wales, Australia
- Department of Upper Gastrointestinal Surgery, Bankstown-Lidcombe Hospital, Bankstown, Sydney, New South Wales, Australia
| | - Tao Yang
- SydPath, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia
| | - Leonardo D Santos
- Department of Anatomical Pathology, Sydney South West Pathology Service, Liverpool Hospital, Liverpool, Sydney, New South Wales, Australia
| | - Darren Pavey
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
- Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Omar Sharaiha
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
- Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Owen McKay
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
- Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Hugh Dixson
- South Western Sydney Clinical School, University of New South Wales, Liverpool, Sydney, New South Wales, Australia
- Department of Nuclear Medicine, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Wei Xuan
- Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia
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Parameshwaran K, Sharma P, Rajendra S, Stelzer-Braid S, Xuan W, Rawlinson WD. Circulating human papillomavirus DNA detection in Barrett's dysplasia and esophageal adenocarcinoma. Dis Esophagus 2019; 32:5532832. [PMID: 31313804 DOI: 10.1093/dote/doz064] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/12/2019] [Accepted: 06/22/2019] [Indexed: 02/07/2023]
Abstract
There is evidence to suggest that human papillomaviruses (HPV) are associated with Barrett's dysplasia and esophageal adenocarcinoma. In other HPV-linked cancers such as cervical and oropharyngeal cancer, circulating HPV DNA is a potential biomarker to assist in tumor diagnosis and management. This study aimed to determine whether circulating HPV DNA was detectable in patients with Barrett's dysplasia and esophageal adenocarcinoma, and if so, whether there is any correlation with esophageal tissue HPV status. Plasma from 138 patients representing esophageal adenocarcinoma (N = 41), Barrett's dysplasia (N = 48) and hospital controls (N = 49) were analyzed for the presence of circulating HPV DNA using droplet-digital PCR targeting the E7 gene of HPV types 16 and 18. Circulating HPV DNA was detected in 11/138 (8.0%) study subjects including 1/49 (2.0%) hospital controls, 4/48 (8.3%) Barrett's dysplasia patients, and 6/41 (14.6%) esophageal adenocarcinoma patients. Detection of circulating HPV DNA was higher in patients with HPV-positive esophageal tissue (6/35, 17.1%) compared to those with HPV-negative specimens (5/103; 4.9%) (OR = 4.06; 95% CI 1.15-14.25; P = 0.020). The highest rates of detection occurred in esophageal adenocarcinoma patients, particularly those with invasive tumors that had breached the esophageal submucosa, had regional lymph node involvement or metastatic disease. Circulating HPV DNA was detectable in a subset of Barrett's dysplasia and esophageal adenocarcinoma patients. Detection was associated with tissue HPV positivity and possibly disease severity.
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Affiliation(s)
- K Parameshwaran
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research.,South Western Sydney Clinical School
| | - P Sharma
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research.,South Western Sydney Clinical School
| | - S Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research.,South Western Sydney Clinical School.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney
| | - S Stelzer-Braid
- School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Women's and Children's Health, Faculties of Medicine and Science, University of New South Wales.,Serology and Virology Division (SAViD) NSW Health Pathology, Microbiology Department, Randwick NSW, Australia
| | - W Xuan
- South Western Sydney Clinical School.,Ingham Institute for Applied Medical Research
| | - W D Rawlinson
- School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Women's and Children's Health, Faculties of Medicine and Science, University of New South Wales.,Serology and Virology Division (SAViD) NSW Health Pathology, Microbiology Department, Randwick NSW, Australia
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26
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Mor A, Kobus K, Leszczyńska U, Reszeć J. Differentiating dysplasia markers in Barrette sophagus and adenocarcinoma. POSTEP HIG MED DOSW 2019. [DOI: 10.5604/01.3001.0013.5643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). This precancerous lesion can transform into low-grade and high-grade dysplasia, which may develop in the EAC. Therefore, the issues of dysplasia detection and monitoring and early diagnostics for the presence of EAC foci are extremely important factors in the surveillance of patients with BE progression. Histopathological examinations are regarded as the gold standard in the BE progression evaluation. They posses a large clinical utility in the identification of dysplasia and cancer risk stratification in patients with the BE. However, this method is a very subjective, and is heavily dependent on the knowledge and experience of the person conducting it. Therefore, it seems to be important to implement in the BE progression diagnostics sensitive and specific biomarkers that could be used as complementary tests. They could improve detection, stratification and monitoring of the progression of BE and the detection of the EAC early stages. Literature data concerning markers distinguishing between different stages of Barrett’s-related dysplasia and cancer is very scarce. In this article there we collected and characterized the most important data. Apart from this, there is a fairly large group of proteins and genes. Their expression levels allow for the detection of changes during the development of the BE progression. No studies have been carried out yet for their usefulness in differentiating between types of BE-related dysplasia and EAC, but we know that some of them could be useful as auxiliary markers differentiating between different stages of dysplasia and EAC. The article discusses those with the greatest potential.
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Affiliation(s)
- Adrian Mor
- Zakład Patomorfologii Lekarskiej Uniwersytetu Medycznego w Białymstoku, Białystok, Polska
| | - Krzysztof Kobus
- Samodzielny Publiczny Zakład Opieki Zdrowotnej w Sokółce, Oddział Chirurgii, Sokółka, Polska
| | - Urszula Leszczyńska
- Zakład Patomorfologii Lekarskiej Uniwersytetu Medycznego w Białymstoku, Białystok, Polska
| | - Joanna Reszeć
- Zakład Patomorfologii Lekarskiej Uniwersytetu Medycznego w Białymstoku, Białystok, Polska
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Wu Q, Wu Z, Bao C, Li W, He H, Sun Y, Chen Z, Zhang H, Ning Z. Cancer stem cells in esophageal squamous cell cancer. Oncol Lett 2019; 18:5022-5032. [PMID: 31612013 PMCID: PMC6781610 DOI: 10.3892/ol.2019.10900] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 05/29/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are hypothesized to govern the origin, progression, drug resistance, recurrence and metastasis of human cancer. CSCs have been identified in nearly all types of human cancer, including esophageal squamous cell cancer (ESCC). Four major methods are typically used to isolate or enrich CSCs, including: i) fluorescence-activated cell sorting or magnetic-activated cell sorting using cell-specific surface markers; ii) stem cell markers, including aldehyde dehydrogenase 1 family member A1; iii) side population cell phenotype markers; and iv) microsphere culture methods. ESCC stem cells have been identified using a number of these methods. An increasing number of stem cell signatures and pathways have been identified, which have assisted in the clarification of molecular mechanisms that regulate the stemness of ESCC stem cells. Certain viruses, such as human papillomavirus and hepatitis B virus, are also considered to be important in the formation of CSCs, and there is a crosstalk between stemness and viruses-associated genes/pathways, which may suggest a potential therapeutic strategy for the eradication of CSCs. In the present review, findings are summarized along these lines of inquiry.
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Affiliation(s)
- Qian Wu
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China.,Nurse School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Zhe Wu
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Cuiyu Bao
- Nurse School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Wenjing Li
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Hui He
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Yanling Sun
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Zimin Chen
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Hao Zhang
- Basic Medical School, Ji'nan University Medical School, Guangzhou, Guangdong 510632, P.R. China
| | - Zhifeng Ning
- Basic Medical School, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
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Rajendra S, Sharma P. Transforming human papillomavirus infection and the esophageal transformation zone: prime time for total excision/ablative therapy? Dis Esophagus 2019; 32:5477363. [PMID: 31304554 DOI: 10.1093/dote/doz008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
High-risk human papillomavirus (hr-HPV) infection is causal for almost all cervical malignancy (both squamous and adenocarcinoma), 90% of anal neoplasia, 70% of penile tumors, and 25% of head and neck cancers. The shared immunogenetics of cervical and esophageal malignancy suggests that HPV infection could well be a common denominator in the etiology of both cancers. In this regard, we have demonstrated that transcriptionally active hr-HPV (genotypes 16 and 18) is strongly associated with Barrett's dysplasia and esophageal adenocarcinoma. Increasing hr-HPV viral load and integration status has been linked with greater disease severity along the Barrett metaplasia-dysplasia-adenocarcinoma sequence as has been demonstrated in cervical intraepithelial neoplasia and cancer. HPV infections in both the cervix and esophagus are both focal, i.e., present in greater quantities at the squamocolumnar junction (SCJ). HPV affinity is to junctional tissue, as basal cells are particularly accessible at the squamocolumnar transformation zone and especially susceptible to this viral infection. We have postulated that progressive acid damage to the esophagus increases the likelihood of mucosal breaks enabling the virus to enter the basal layer of the transformation zone. The SCJ is the transformation zone of the esophagus and is strikingly similar to the transition zone (ectoendocervical SCJ) of the uterine cervix where almost all high-grade cervical lesions and cancers arise including 80% of adenocarcinomas. These transition zone cells exhibit features of squamous epithelium as well as glandular cells, which have been described in both Barrett's esophagus and cervical mucosa. Barrett's esophagus (BE) is derived from a discrete population of embryonic cells residing at the SCJ. There is loss of SCJ immune-phenotype following excision without regeneration at other junctional sites. Prevention of cervical cancer in up to 80-95% of patients with screen-detected CIN is dependent on the excision/ablation of the entire transformation zone. The persistence of hr-HPV 16/18 following eradication of CIN is a significant risk factor for recurrence. Similarly, we have demonstrated that persistent hr-HPV infection 16/18 and p53 overexpression are associated with treatment failure after endoscopic ablation of BD/EAC. Thus, we believe that excision/ablation of the SCJ in patients with BD/intramucosal EAC should be performed to reduce the potential malignant risk. We propose to test this hypothesis by a multicenter randomized controlled trial whereby patients (both HPV positive and those which are virus negative) will be allocated into two arms: complete excision of the SCJ via endoscopic mucosal resection (EMR) in addition to radiofrequency ablation (RFA) ± EMR of BD/intramucosal EAC (experimental arm) versus current standard of care (RFA ± EMR) of said lesions. Treatment efficacy in both groups will be evaluated by comparing disease elimination, regression/progression, and recurrence (if any). All patients would be entered into an intensive endoscopic surveillance protocol (biannually) for at least 2 years with lesional/neosquamous biopsies to compare the recurrence rate of both dysplasia/neoplasia in both arms. Viral (HPV DNA/p16INK4A/E6/E7 mRNA) and host biomarkers (e.g., p53) will be analyzed both at baseline and posttreatment intervals. A positive study would initiate development of tools best suited for SCJ destruction.
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Affiliation(s)
- S Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - P Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Centre and University of Kansas City, Missouri, USA
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Hošnjak L, Poljak M. A systematic literature review of studies reporting human papillomavirus (HPV) prevalence in esophageal carcinoma over 36 years (1982–2017). ACTA DERMATOVENEROLOGICA ALPINA PANNONICA ET ADRIATICA 2018. [DOI: 10.15570/actaapa.2018.26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Rajendra S, Xuan W, Merrett N, Sharma P, Sharma P, Pavey D, Yang T, Santos LD, Sharaiha O, Pande G, Cosman P, Wu X, Wang B. Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection. JAMA Netw Open 2018; 1:e181054. [PMID: 30646096 PMCID: PMC6324261 DOI: 10.1001/jamanetworkopen.2018.1054] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
IMPORTANCE High-risk human papillomavirus (HPV) has been associated with Barrett dysplasia and esophageal adenocarcinoma. Nevertheless, the prognostic significance of esophageal tumor HPV status is unknown. OBJECTIVE To determine the association between HPV infection and related biomarkers in high-grade dysplasia or esophageal adenocarcinoma and survival. DESIGN, SETTING, AND PARTICIPANTS Retrospective case-control study. The hypothesis was that HPV-associated esophageal tumors would show a favorable prognosis (as in viral-positive head and neck cancers). Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction, in situ hybridization for E6 and E7 messenger RNA (mRNA), and immunohistochemistry for the proteins p16INK4A and p53. Sequencing of TP53 was also undertaken. The study took place at secondary and tertiary referral centers, with 151 patients assessed for eligibility and 9 excluded. The study period was from December 1, 2002, to November 28, 2017. MAIN OUTCOMES AND MEASURES Disease-free survival (DFS) and overall survival (OS). RESULTS Among 142 patients with high-grade dysplasia or esophageal adenocarcinoma (126 [88.7%] male; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. Patients who were HPV positive mostly had high p16INK4A expression, low p53 expression, and wild-type TP53. There were more Tis, T1, and T2 tumors in HPV-positive patients compared with HPV-negative patients (75.7% vs 54.3%; difference, 21.4%; 95% CI, 4.6%-38.2%; P = .02). Mean DFS was superior in the HPV-positive group (40.3 vs 24.1 months; difference, 16.2 months; 95% CI, 5.7-26.8; P = .003) as was OS (43.7 vs 29.8 months; difference, 13.9 months; 95% CI, 3.6-24.3; P = .009). Recurrence or progression was reduced in the HPV-positive cohort (24.3% vs 58.1%; difference, -33.8%; 95% CI, -50.5% to -17.0%; P < .001) as was distant metastasis (8.1% vs 27.6%; difference, -19.5%; 95% CI, -31.8% to -7.2%; P = .02) and death from esophageal adenocarcinoma (13.5% vs 36.2%; difference, -22.7%; 95% CI, -37.0% to -8.3%; P = .01). Positive results for HPV and transcriptionally active virus were both associated with a superior DFS (hazard ratio [HR], 0.33; 95% CI, 0.16-0.67; P = .002 and HR, 0.44; 95% CI, 0.22-0.88; P = .02, respectively [log-rank test]). Positivity for E6 and E7 mRNA, high p16INK4A expression, and low p53 expression were not associated with improved DFS. On multivariate analysis, superior DFS was demonstrated for HPV (HR, 0.39; 95% CI, 0.18-0.85; P = .02), biologically active virus (HR, 0.36; 95% CI, 0.15-0.86; P = .02), E6 and E7 mRNA (HR, 0.36; 95% CI, 0.14-0.96; P = .04), and high p16 expression (HR, 0.49; 95% CI, 0.27-0.89; P = .02). CONCLUSIONS AND RELEVANCE Barrett high-grade dysplasia and esophageal adenocarcinoma in patients who are positive for HPV are distinct biological entities with a favorable prognosis compared with viral-negative esophageal tumors. Confirmation of these findings in larger cohorts with more advanced disease could present an opportunity for treatment de-escalation in the hope of reducing toxic effects without deleteriously affecting survival.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, New South Wales, Australia
| | - Wei Xuan
- Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Neil Merrett
- Discipline of Surgery, School of Medicine, Western Sydney University, Penrith, New South Wales, Australia
- Department of Upper Gastrointestinal Surgery, Bankstown-Lidcombe Hospital, Bankstown, New South Wales, Australia
| | - Preeti Sharma
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas School of Medicine, Kansas City, Missouri
| | - Darren Pavey
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, New South Wales, Australia
| | - Tao Yang
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia
- SydPath, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
| | - Leonardo D. Santos
- Department of Anatomical Pathology, Sydney South West Pathology Service, Liverpool Hospital, Liverpool, New South Wales, Australia
| | - Omar Sharaiha
- South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, New South Wales, Australia
| | - Girish Pande
- Department of Surgery, Launceston General Hospital, Launceston, Tasmania, Australia
| | - Peter Cosman
- Graduate School of Medicine and Illawara Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia
| | - Xiaojuan Wu
- Immunohistochemistry and Molecular Pathology Unit, NSW Health Pathology, Liverpool, New South Wales, Australia
| | - Bin Wang
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, New South Wales, Australia
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El‐Zimaity H, Di Pilato V, Novella Ringressi M, Brcic I, Rajendra S, Langer R, Dislich B, Tripathi M, Guindi M, Riddell R. Risk factors for esophageal cancer: emphasis on infectious agents. Ann N Y Acad Sci 2018; 1434:319-332. [DOI: 10.1111/nyas.13858] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/30/2018] [Accepted: 04/24/2018] [Indexed: 12/17/2022]
Affiliation(s)
| | - Vincenzo Di Pilato
- Department of Clinical and Experimental MedicineUniversity of Florence Florence Italy
| | - Maria Novella Ringressi
- Department of Surgery and Translational MedicineUniversity of Florence Florence Italy
- Gastrointestinal Surgery UnitFlorence Careggi University Hospital Florence Italy
| | - Iva Brcic
- Institute of PathologyMedical University of Graz Graz Austria
| | - Shanmugarajah Rajendra
- Gastro‐Intestinal Viral Oncology GroupIngham Institute for Applied Medical Research, Liverpool Sydney New South Wales Australia
- South Western Sydney Clinical SchoolUniversity of New South Wales, Kensington Sydney New South Wales Australia
- Department of Gastroenterology & HepatologyBankstown‐Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown Sydney New South Wales Australia
| | - Rupert Langer
- Institute of PathologyUniversity of Bern Bern Switzerland
| | - Bastian Dislich
- Institute of PathologyKantonsspital Baselland Liestal Switzerland
| | - Monika Tripathi
- Cambridge University HospitalsNHS Foundation Trust Cambridge UK
| | - Maha Guindi
- Department of Pathology and laboratory MedicineCedars‐Sinai Medical Center Los Angeles California
| | - Robert Riddell
- Department of Pathology and Laboratory MedicineMount Sinai Hospital Toronto Ontario Canada
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A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine. Br J Cancer 2018; 118:1302-1312. [PMID: 29700411 PMCID: PMC5959925 DOI: 10.1038/s41416-018-0049-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 02/05/2018] [Accepted: 02/07/2018] [Indexed: 12/19/2022] Open
Abstract
Background Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. Methods In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Results Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Conclusions Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits.
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Costa NR, Gil da Costa RM, Medeiros R. A viral map of gastrointestinal cancers. Life Sci 2018; 199:188-200. [PMID: 29476768 DOI: 10.1016/j.lfs.2018.02.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 02/16/2018] [Indexed: 12/12/2022]
Abstract
Cancers of the gastrointestinal tract (GIT) are expected to account for approximately 20% of all cancers in 2017. Apart from their high incidence, GIT cancers show high mortality rates, placing these malignancies among the most prominent public health issues of our time. Cancers of the GIT are the result of a complex interplay between host genetic factors and environmental factors and frequently arise in the context of a continued active inflammatory response. Several tumor viruses are able to elicit such chronic inflammatory responses. In fact, several viruses have an impact on GIT tumor initiation and progression, as well as on patients' response to therapy and prognosis, through direct and indirect mechanisms. In this review, we have gathered information on different viruses' rates of infection, viral-driven specific carcinogenesis mechanisms and viral-related impact on the prognosis of cancers of the GIT (specifically in organs that have an interface with the environment - esophagus, stomach, intestines and anus). Overall, while some viral infections show a strong causal relation with specific gastrointestinal cancers, these represent a relatively small fraction of GIT malignancies. Other types of cancer, like Esophageal Squamous Cell Carcinoma, require further studies to confirm the carcinogenic role of some viral agents.
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Affiliation(s)
- Natália R Costa
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal.
| | - Rui M Gil da Costa
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; LEPABE, Faculty of Engineering, University of Porto, Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO-Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO-Porto), Porto, Portugal; Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal; CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal; Research Department, Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro-Núcleo Regional do Norte), Porto, Portugal
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Lam SY, Yu J, Wong SH, Peppelenbosch MP, Fuhler GM. The gastrointestinal microbiota and its role in oncogenesis. Best Pract Res Clin Gastroenterol 2017; 31:607-618. [PMID: 29566903 DOI: 10.1016/j.bpg.2017.09.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/03/2017] [Indexed: 02/07/2023]
Abstract
Advances in research techniques have made it possible to map the microbial communities in the gastrointestinal (GI) tract, where the majority of bacteria in the human body reside. Disturbances in these communities are referred to as dysbiosis and have been associated with GI cancers. Although dysbiosis is observed in several GI malignancies, the specific role of these changes has not been understood to the extent of Helicobacter pylori (HP) in gastric cancer (GC). This review will address the bacterial communities along the GI tract, from the oral cavity to the anal canal, particularly focusing on bacterial dysbiosis and carcinogenesis. Just as non-HP bacteria in the stomach may interact with HP in gastric carcinogenesis, the same may hold true for other GI tract malignancies, where an interplay between microbes in carcinogenesis seems conceivable, especially in colorectal cancer (CRC). In the last part of this review we will discuss the potential mechanisms of bacterial dysbiosis in GI carcinogenesis.
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Affiliation(s)
- S Y Lam
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - J Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - S H Wong
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences and CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - M P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | - G M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Brochard C, Ducancelle A, Pivert A, Bodin M, Ricard A, Coron E, Couffon C, Dib N, Luet D, Musquer N, Rhun ML, Bertrais S, Michalak S, Lunel-Fabiani F, Cesbron-Metivier E, Caroli-Bosc FX. Human papillomavirus does not play a role in the Barrett esophagus: a French cohort. Dis Esophagus 2017; 30:1-7. [PMID: 28881904 DOI: 10.1093/dote/dox088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 06/07/2017] [Indexed: 12/11/2022]
Abstract
The role of human papillomavirus (HPV) in Barrett's esophagus (BE) has been examined but remains unclear. The purpose of the study is to dispute the connection between HPV and BE in a prospective case-control study. Biopsies were performed above and inside the Barrett's segment for BE patients and in the distal third of the esophagus for control patients for histological interpretation and for virological analysis. Biopsies for virological analysis were placed in a virus transport medium and immediately frozen in liquid nitrogen. Virological analysis involved real-time PCR using the SyBr® green protocol with modified SPF10 general primers. A total of 180 patients (119 control and 61 BE, respectively) were included. In BE patients, 31, 18, and 12 patients had, respectively, no dysplasia, low-grade dysplasia, and high grade dysplasia. Overall, nine were found to be HPV positive: five were control patients and four BE patients. HPV positive status was not associated with BE. No factors were associated with HPV, in particular the degree of BE dysplasia. HPV infection appears unlikely to be significant in the etiology of BE compared with control patients. (ClinicalTrials.gov, Number NCT02549053).
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Affiliation(s)
- C Brochard
- Gastroenterology and Hepatology Department, University Hospital.,INSERM U991, Rennes.,INSERM U913.,Gastroenterology and Hepatology Department
| | | | | | | | - A Ricard
- Gastroenterology and Hepatology Department
| | - E Coron
- INSERM U913.,Gastroenterology, Hepatology and Nutritional Support, University Hospital, Nantes
| | - C Couffon
- Gastroenterology and Hepatology Department
| | - N Dib
- Gastroenterology and Hepatology Department
| | - D Luet
- Gastroenterology and Hepatology Department
| | - N Musquer
- Gastroenterology, Hepatology and Nutritional Support, University Hospital, Nantes
| | - M Le Rhun
- Gastroenterology, Hepatology and Nutritional Support, University Hospital, Nantes
| | - S Bertrais
- HIFIH Laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France
| | - S Michalak
- HIFIH Laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France.,Pathology Department, University Hospital
| | - F Lunel-Fabiani
- Virology Department.,HIFIH Laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France
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Mirzaei H, Goudarzi H, Eslami G, Faghihloo E. Role of viruses in gastrointestinal cancer. J Cell Physiol 2017; 233:4000-4014. [PMID: 28926109 DOI: 10.1002/jcp.26194] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/08/2017] [Indexed: 12/22/2022]
Abstract
Gastrointestinal cancers are a global public health problem, which represent a vast majority of all cancer-caused deaths in both men and women. On the other hand, viral pathogens have been long implicated as etiological factors in the onset of certain human cancers, including gastrointestinal tumors. In this regard, Human Papilloma Virus (HPV), Epstein-Barr Virus (EBV), and John Cunningham Virus (JCV) have been more strongly suggested to be involved in gastrointestinal carcinogenesis; so that, the association of HPV with oropharyngeal and anal cancers and also the association of EBV with gastric cancer have been etiologically confirmed by epidemiological and experimental investigations. Although, the association of other viruses is less evident, but may rely on co-factors for their oncogenic roles. Therefore, to improve the prevention and treatment of these classes of cancer, their association with viral agents as potential risk factors should be investigated with care. In this respect, the present review has focused on the existing literature on the subject of viral involvement in gastrointestinal tumorgenesis, by covering and discussing various gastrointestinal cancers, corresponding viral agents and their oncogenic aspects and then summarizing evidences either supporting or rejecting a causal role of these pathogens in gastrointestinal malignancies.
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Affiliation(s)
- Habibollah Mirzaei
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Gita Eslami
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Rajendra S, Yang T, Xuan W, Sharma P, Pavey D, Lee CS, Le S, Collins J, Wang B. Active human papillomavirus involvement in Barrett's dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway. Int J Cancer 2017; 141:2037-2049. [PMID: 28722212 DOI: 10.1002/ijc.30896] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 06/14/2017] [Accepted: 07/11/2017] [Indexed: 12/15/2022]
Abstract
We have previously demonstrated that transcriptionally active high-risk HPV (hr-HPV) is strongly incriminated in Barrett's dysplasia (BD) and oesophageal adenocarcinoma (OAC) using mainly fresh frozen tissue. This study aimed to identify biomarkers of active HPV infection in Barrett's metaplasia, (BM)/BD/OAC by immunohistochemical staining (IHC) of formalin-fixed paraffin embedded (FFPE) tissue for aberrations of p53 and the retinoblastoma (pRb) pathway, which are targets for the viral oncoproteins, E6/E7, respectively. Prospectively, BM (n = 81)/BD (n = 72)/OAC (n = 65) FFPE specimens were subjected to IHC staining for pRb, p16INK4A , cyclin D1 , p53 and RNA in-situ hybridization for E6/E7 transcripts. HPV DNA was determined via PCR in fresh frozen specimens. Viral load measurement (real-time PCR) and Next Generation Sequencing of TP53 was performed. Of 218 patients, 56 were HPV DNA positive [HPV16 (n = 42), 18 (n = 13), 6 (n = 1)]. Viral load was low. Transcriptionally active HPV (DNA+ /RNA+ ) was only found in the dysplastic and adenocarcinoma group (n = 21). The majority of HPV DNA+ /RNA+ BD/OAC were characterized by p 16highINK4A (14/21, 66.7%), pRblow (15/21, 71.4%) and p53low (20/21, 95%) and was significantly different to controls [combination of HPV DNA- /RNA- (n = 94) and HPV DNA+ /RNA- cohorts (n = 22)]. p53low had the strongest association with DNA+ /RNA+ oesophageal lesions (OR = 23.5, 95% CI = 2.94-187.8, p = 0.0029). Seventeen HPV DNA+ /RNA+ BD/OAC identified as p53low, were sequenced and all but one exhibited wild-type status. pRblow /p53low provided the best balance of strength of association (OR = 8.0, 95% CI = 2.6-25.0, p = 0.0003) and sensitivity (71.4%)/specificity (71.6%) for DNA+ /RNA+ BD/OAC. Active HPV involvement in BD/OAC is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, NSW, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, NSW, Australia
| | - Tao Yang
- Department of Anatomical Pathology, South Western Sydney Area Pathology Service, Liverpool, Sydney, NSW, Australia.,Faculty of Medicine, Discipline of Pathology, School of Medicine, University of Western Sydney, NSW, Australia
| | - Wei Xuan
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW, Australia.,Ingham Institute for Applied Medical Research, Liverpool, Sydney, NSW, Australia
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas City, MO
| | - Darren Pavey
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, NSW, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, NSW, Australia
| | - Cheong Soon Lee
- Department of Anatomical Pathology, South Western Sydney Area Pathology Service, Liverpool, Sydney, NSW, Australia.,Faculty of Medicine, Discipline of Pathology, School of Medicine, University of Western Sydney, NSW, Australia
| | - Son Le
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, NSW, Australia
| | - Josephine Collins
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW, Australia.,Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, NSW, Australia
| | - Bin Wang
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, NSW, Australia.,South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, NSW, Australia
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Kunzmann AT, Graham S, McShane CM, Doyle J, Tommasino M, Johnston B, Jamison J, James JA, McManus D, Anderson LA. The prevalence of viral agents in esophageal adenocarcinoma and Barrett's esophagus: a systematic review. Eur J Gastroenterol Hepatol 2017; 29:817-825. [PMID: 28252462 DOI: 10.1097/meg.0000000000000868] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Human papilloma virus (HPV), which may reach the esophagus through orogenital transmission, has been postulated to be associated with esophageal adenocarcinoma (EAC). A systematic review of the literature investigating the prevalence of infectious agents in EAC and Barrett's esophagus (BE) was carried out. METHODS Using terms for viruses and EAC, the Medline, Embase, and Web of Science databases were systematically searched for studies published, in any language, until June 2016 that assessed the prevalence of viral agents in EAC or BE. Random-effects meta-analyses of proportions were carried out to calculate the pooled prevalence and 95% confidence intervals (CIs) of infections in EAC and BE. RESULTS A total of 30 studies were included. The pooled prevalence of HPV in EAC tumor samples was 13% (n=19 studies, 95% CI: 2-29%) and 26% (n=6 studies, 95% CI: 3-59%) in BE samples. HPV prevalence was higher in EAC tissue than in esophageal tissue from healthy controls (n=5 studies, pooled odds ratio=3.31, 95% CI: 1.15-9.50). The prevalence of Epstein-Barr virus (EBV) in EAC was 6% (n=5, 95% CI: 0-27%). Few studies have assessed other infectious agents. For each of the analyses, considerable between-study variation was observed (I=84-96%); however, sensitivity analyses did not show any major sources of heterogeneity. CONCLUSION The prevalence of HPV and EBV in EAC is low compared with other viral-associated cancers, but may have been hampered by small sample sizes and detection methods susceptible to fixation processes. Additional research with adequate sample sizes and high-quality detection methods is required.
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Affiliation(s)
- Andrew T Kunzmann
- aCancer Epidemiology and Health Services Research Group, Centre for Public Health bNorthern Ireland Biobank, Centre for Cancer Research and Cell Biology, Queens University Belfast cRoyal Victoria Hospital, Belfast Health and Social Care Trust dAntrim Area Hospital Laboratory, Department of Cellular Cytopathology and Molecular Pathology, Northern Health and Social Care Trust, Northern Ireland eInfections and Cancer Biology Group, International Agency for Research on Cancer, World Health Organization, Lyon, France
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Abstract
Barrett esophagus (BE) is a precursor lesion for esophageal adenocarcinoma (EAC). Developments in imaging and molecular markers, and endoscopic eradication therapy, are available to curb the increase of EAC. Endoscopic surveillance is recommended, despite lack of data. The cancer risk gets progressively downgraded, raising questions about the understanding of risk factors and molecular biology involved. Recent data point to at least 2 carcinogenic pathways operating in EAC. The use of p53 overexpression and high-risk human papillomavirus may represent the best chance to detect progressors. Genome-wide technology may provide molecular signatures to aid diagnosis and risk stratification in BE.
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Bucchi D, Stracci F, Buonora N, Masanotti G. Human papillomavirus and gastrointestinal cancer: A review. World J Gastroenterol 2016; 22:7415-7430. [PMID: 27672265 PMCID: PMC5011658 DOI: 10.3748/wjg.v22.i33.7415] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/29/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. Exposure to HPV is very common, and an estimated 65%-100% of sexually active adults are exposed to HPV in their lifetime. The majority of HPV infections are asymptomatic, but there is a 10% chance that individuals will develop a persistent infection and have an increased risk of developing a carcinoma. The International Agency for Research on Cancer has found that the following cancer sites have a strong causal relationship with HPV: cervix uteri, penis, vulva, vagina, anus and oropharynx, including the base of the tongue and the tonsils. However, studies of the aetiological role of HPV in colorectal and esophageal malignancies have conflicting results. The aim of this review was to organize recent evidence and issues about the association between HPV infection and gastrointestinal tumours with a focus on esophageal, colorectal and anal cancers. The ultimate goal was to highlight possible implications for prognosis and prevention.
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Antonsson A, Knight L, Whiteman DC. Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens-Reply. Cancer Epidemiol 2016; 43:120. [PMID: 27246504 DOI: 10.1016/j.canep.2016.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 05/08/2016] [Indexed: 11/18/2022]
Affiliation(s)
- Annika Antonsson
- Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
| | - Lani Knight
- Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - David C Whiteman
- Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia
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Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens-Letter. Cancer Epidemiol 2016; 43:119. [PMID: 27230106 DOI: 10.1016/j.canep.2016.05.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/08/2016] [Indexed: 11/22/2022]
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Human papillomavirus not detected in esophageal adenocarcinoma tumor specimens. Cancer Epidemiol 2016; 41:96-8. [PMID: 26895084 DOI: 10.1016/j.canep.2016.01.014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 01/28/2016] [Accepted: 01/31/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Human papillomavirus (HPV) has been implicated as playing a causal role in Barrett's esophagus, the metaplastic precursor to esophageal adenocarcinomas (EAC) and gastro-esophageal junction adenocarcinomas (GEJACs). We evaluated the presence of HPV DNA in EACs and GEJACs. STUDY DESIGN We analyzed 241 histologically confirmed archived EAC and GEJAC tissue specimens from a population-based study in Australia. Samples were tested by PCR for DNA quality (β-globin) and for the presence of HPV DNA. RESULTS DNA yield and quality was satisfactory in 97% (233/241; 201 EAC, 32 GEJAC). Each sample was tested three times for HPV DNA, but none of the 233 tumor specimens tested positive. CONCLUSIONS We found no evidence of HPV DNA in esophageal adenocarcinoma tumor cells. HPV is unlikely to cause EAC or GEJAC.
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Türkay DÖ, Vural Ç, Sayan M, Gürbüz Y. Detection of human papillomavirus in esophageal and gastroesophageal junction tumors: A retrospective study by real-time polymerase chain reaction in an instutional experience from Turkey and review of literature. Pathol Res Pract 2015; 212:77-82. [PMID: 26608416 DOI: 10.1016/j.prp.2015.10.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 08/10/2015] [Accepted: 10/20/2015] [Indexed: 02/07/2023]
Abstract
Esophageal cancer is a poor-prognosis malignancy that ranks eighth among all cancer types, and its prevalence shows differences among geographical regions. Although the most important risk factors for esophageal carcinoma are alcohol and smoking, viral infections, particularly HPV infection, are also considered among etiological agents. Our study aims to detect the presence of HPV in esophageal cancers in our patient population and to investigate its correlation with clinico-pathological parameters. We investigated the presence of HPV-DNA by real-time polymerase chain reaction in a total of 52 patients with esophageal cancer. Subtype analysis was performed in positive cases and was correlated with selected clinico-pathological parameters. Five (9.6%) of 52 tumor samples, 3 squamous cell carcinomas (3/33 cases) and 2 adenocarcinomas (2/19 cases), were HPV-DNA-positive. Subtype analysis could be performed in four HPV-DNA-positive cases, of which three were HPV type-39 and 1 was type-16. The Marmara region, where the present study was carried out, is a region with low-moderate risk for esophageal cancer, and the prevalence of HPV-DNA in these tumors is similar to the prevalence of HPV-DNA reported in the literature for regions with similar risk. In conclusion, we detected HPV DNA in a subset of esophageal and gastroesophageal junction tumors. HPV infection may have a role in esophageal carcinogenesis and high-risk HPV subtypes can particularly be considered among risk factors since the prevalence of high risk HPV infection has also been found to be increased in regions with a high risk for esophageal cancer compared to low-moderate risk regions.
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Affiliation(s)
- Düriye Özer Türkay
- Department of Pathology, Ankara Numune Research and Education Hospital, Ankara, Turkey
| | - Çiğdem Vural
- Department of Pathology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey.
| | - Murat Sayan
- Kocaeli University Hospital, Clinical Laboratory, PCR Unit, Kocaeli, Turkey; Near East University, Research Center of Experimental Health Sciences, Nicasia, Northern Cyprus
| | - Yeşim Gürbüz
- Department of Pathology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
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Rajendra S, Wang B, Merrett N, Sharma P, Humphris J, Lee HC, Wu J. Genomic analysis of HPV-positive versus HPV-negative oesophageal adenocarcinoma identifies a differential mutational landscape. J Med Genet 2015; 53:227-31. [PMID: 26470716 DOI: 10.1136/jmedgenet-2015-103411] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/12/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND High-risk human papillomavirus (hr-HPV) has been implicated in a subset of patients with oesophageal adenocarcinoma (OAC). We therefore hypothesised that HPV associated OAC may have distinct genomic aberrations compared with viral negative oesophageal cancer. METHODS Whole exome sequencing was performed to explore the mutational landscape and potential molecular signature of HPV-positive versus HPV-negative OAC. Four hr-HPV-positive and 8 HPV-negative treatment-naive fresh-frozen OAC tissue specimens and matched normal tissue were analysed to identify somatic genomic mutations. Data were subjected to cancer driver gene identification and pathway analysis. RESULTS The HPV-positive cohort harboured approximately 50% less non-silent somatic mutations than the virus-negative patients with oesophageal cancer (1.31 mutations/Mb vs 2.56 mutations/Mb, p=0.048). TP53 aberrations were absent in the HPV-positive OAC group whereas 50% of the HPV-negative patients with OAC exhibited TP53 mutations. HPV-negative cancers were enriched with non-silent mutations in cancer driver genes, but not HPV-positive tumours. Enriched A>C transversions at adenine-adenine (AA) dinucleotide was observed in 5/7 Siewert class I OAC samples but none (0/5) in Siewert class II tumours (p=0.027). CONCLUSIONS These findings demonstrate distinct genomic differences between HPV-positive and HPV-negative OACs indicating different biological mechanisms of tumour formation.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Sydney, New South Wales, Australia
| | - Bin Wang
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Neil Merrett
- Department of Surgery, Bankstown Hospital, Sydney, New South Wales, Australia Discipline of Surgery, University of Western Sydney, Campbelltown, New South Wales, Australia
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas City, Kansas City, Missouri, USA
| | - Jeremy Humphris
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Sydney, New South Wales, Australia
| | - Hong Ching Lee
- Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia
| | - Jianmin Wu
- Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia
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Does Human Papillomavirus Cause Esophageal Adenocarcinoma? Clin Gastroenterol Hepatol 2015; 13:1369-70. [PMID: 25543103 DOI: 10.1016/j.cgh.2014.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 12/17/2014] [Accepted: 12/18/2014] [Indexed: 02/07/2023]
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Rajendra S, Wang B, Pavey D, Sharma P, Yang T, Lee CS, Gupta N, Ball MJ, Gill RS, Wu X. Persistence of Human Papillomavirus, Overexpression of p53, and Outcomes of Patients After Endoscopic Ablation of Barrett's Esophagus. Clin Gastroenterol Hepatol 2015; 13:1364-1368.e5. [PMID: 25460562 DOI: 10.1016/j.cgh.2014.11.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 10/31/2014] [Accepted: 11/04/2014] [Indexed: 02/07/2023]
Abstract
We investigated the role of high-risk human papillomavirus (hr-HPV) in patients with Barrett's dysplasia and adenocarcinoma (EAC). Clearance vs persistence of HPV (DNA, E6 or E7 mRNA, and p16INK4A protein) and overexpression or mutation of p53 were determined for 40 patients who underwent endotherapy for Barrett's dysplasia or EAC. After ablation, dysplasia or neoplasia was eradicated in 34 subjects (24 squamous, 10 intestinal metaplasia). Six patients had detectable lesions after treatment; 2 were positive for transcriptionally active hr-HPV, and 4 had overexpression of p53. Before endotherapy, 15 patients had biologically active hr-HPV, 13 cleared the infection with treatment, and dysplasia or EAC was eliminated from 12 patients. One patient who cleared HPV after ablation acquired a p53 mutation, and their cancer progressed. Of 13 patients with overexpression of p53 before treatment, 10 cleared the p53 abnormality after ablation with eradication of dysplasia or neoplasia, whereas 3 of 13 had persistent p53 mutation-associated dysplasia after endotherapy (P = .004). Immunohistochemical and sequence analyses of p53 produced concordant results for 36 of 40 samples (90%). Detection of dysplasia or neoplasia after treatment was associated with HPV persistence or continued p53 overexpression.
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Affiliation(s)
- Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia; Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia.
| | - Bin Wang
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia
| | - Darren Pavey
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, Australia; South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales, Australia; Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas City, Missouri
| | - Tao Yang
- Department of Anatomical Pathology, South Western Sydney Area Pathology Service, Liverpool, Sydney, New South Wales, Australia
| | - Cheok Soon Lee
- Department of Anatomical Pathology, South Western Sydney Area Pathology Service, Liverpool, Sydney, New South Wales, Australia; Discipline of Pathology, School of Medicine, University of Western Sydney, Sydney, New South Wales, Australia
| | - Neil Gupta
- Division of Gastroenterology and Nutrition, Loyola University Medical Center, Maywood, Illinois
| | - Madeleine J Ball
- School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia
| | - Raghubinder Singh Gill
- Department of Gastroenterology and Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales, Australia
| | - Xiaojuan Wu
- Department of Anatomical Pathology, South Western Sydney Area Pathology Service, Liverpool, Sydney, New South Wales, Australia
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Abstract
BACKGROUND Esophageal cancer (EC) is the eighth most prevalent malignant tumor and the sixth leading cause of cancer mortality throughout the world. Despite the technical developments in diagnosis and treatment, the 5-year survival rate is still low. The etiology of EC remains poorly understood; multiple risk factors may be involved and account for the great variation in EC incidence in different geographic regions. SUMMARY Infection with carcinogenetic pathogens has been proposed as a risk factor for EC. This review explores the recent studies on the association of human papillomavirus (HPV), Epstein-Barr virus (EBV), Helicobacter pylori and esophageal bacterial biota with EC. KEY MESSAGE Among the above-mentioned pathogens, HPV most likely contributes to esophageal squamous cell carcinoma (ESCC) in high-risk populations. New techniques are being applied to studies on the role of infection in EC, which will inevitably bring novel ideas to the field in the near future. PRACTICAL IMPLICATIONS Multiple meta-analyses support the finding of a higher HPV detection rate in regions associated with high risk for ESCC compared to low-risk areas. A potential role of HPV in the rise of esophageal adenocarcinoma (EAC) was proposed recently. However, further studies are required before a firm conclusion can be drawn. Less work has been done in studying the association between EBV and ESCC, and the results are quite controversial. H. pylori infection is found to be inversely related to EC, which is probably due to the reduced incidence of gastroesophageal reflux disease. Analysis of the esophageal bacterial biota revealed distinct clusters of bacteria in normal and diseased esophagi. A type II microbiome rich in Gram-negative bacteria potentially contributes to EAC by inducing chronic inflammation. Novel findings from such studies as these may benefit public health by justifying anti-infection measures to prevent EC.
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Affiliation(s)
- Wenji Xu
- Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Zhongshu Liu
- Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Quncha Bao
- Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Zhikan Qian
- Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
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