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Singini MG, Muchengeti M, Sitas F, Chen WC, Combes JD, Waterboer T, Clifford GM. Antibodies against high-risk human papillomavirus proteins as markers for noncervical HPV-related cancers in a Black South African population, according to HIV status. Int J Cancer 2024; 155:251-260. [PMID: 38577820 DOI: 10.1002/ijc.34919] [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: 11/07/2023] [Revised: 01/16/2024] [Accepted: 02/06/2024] [Indexed: 04/06/2024]
Abstract
Human papillomavirus (HPV) proteins may elicit antibody responses in the process toward HPV-related malignancy. However, HPV seroepidemiology in noncervical HPV-related cancers remains poorly understood, particularly in populations with a high prevalence of human immunodeficiency virus (HIV). Using a glutathione S-transferase-based multiplex serology assay, antibodies against E6, E7 and L1 proteins of HPV16 and HPV18 were measured in sera of 535 cases of noncervical HPV-related cancers (anal (n = 104), vulval (n = 211), vaginal (n = 49), penile (n = 37) and oropharyngeal (n = 134)) and 6651 non-infection-related cancer controls, from the Johannesburg Cancer Study that recruited Black South African with newly diagnosed cancer between 1995 and 2016. Logistic and Poisson regression models were used to calculate adjusted odds ratios (aOR) and prevalence ratios (aPR) and 95% confidence intervals (CI) in cases versus controls. HPV16 E6 was more strongly associated with noncervical HPV-related cancers than HPV16 L1 or E7, or HPV18 proteins: anal (females (HPV16 E6 aOR = 11.50;95%CI:6.0-22.2), males (aOR = 10.12;95%CI:4.9-20.8), vulval (aOR = 11.69;95%CI:7.9-17.2), vaginal (aOR = 10.26;95%CI:5.0-21), penile (aOR = 18.95;95%CI:8.9-40), and oropharyngeal (females (aOR = 8.95;95%CI:2.9-27.5), males (aOR = 3.49;95%CI:1.8-7.0)) cancers. HPV16-E6 seropositivity ranged from 24.0% to 35.1% in anal, vulval, vaginal and penile cancer but was significantly lower (11.2%) in oropharyngeal cancer. After adjustment for HIV, prevalence of which increased from 22.2% in 1995-2005 to 54.1% in 2010-2016, HPV16 E6 seropositivity increased by period of diagnosis (aPR for 2010-2016 vs. 1995-2006 = 1.84;95%CI:1.1-3.0). Assuming HPV16 E6 seroprevalence reflects HPV attributable fraction, the proportion of certain noncervical-HPV-related cancers caused by HPV is increasing over time in South Africa. This is expected to be driven by the increasing influence of HIV.
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Affiliation(s)
- Mwiza Gideon Singini
- International Agency for Research on Cancer (IARC/WHO), Early Detection, Prevention and Infections Branch, Lyon, France
- National Cancer Registry, National Institute for Communicable Diseases a Division of the National Health Laboratory Service, Johannesburg, South Africa
| | - Mazvita Muchengeti
- National Cancer Registry, National Institute for Communicable Diseases a Division of the National Health Laboratory Service, Johannesburg, South Africa
- School of Public Health, University of the Witwatersrand, Johannesburg, South Africa
- South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Stellenbosch, South Africa
| | - Freddy Sitas
- Center for Primary Health Care and Equity, School of Population Health, University of New South Wales Sydney, Sydney, New South Wales, Australia
- Menzies Center of Health Policy, School of Public Health, University of Sydney, Sydney, New South Wales, Australia
| | - Wenlong Carl Chen
- National Cancer Registry, National Institute for Communicable Diseases a Division of the National Health Laboratory Service, Johannesburg, South Africa
- Strengthening Oncology Services Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Jean-Damien Combes
- International Agency for Research on Cancer (IARC/WHO), Early Detection, Prevention and Infections Branch, Lyon, France
| | - Tim Waterboer
- Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Gary M Clifford
- International Agency for Research on Cancer (IARC/WHO), Early Detection, Prevention and Infections Branch, Lyon, France
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2
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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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3
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Galati L, Chiocca S, Duca D, Tagliabue M, Simoens C, Gheit T, Arbyn M, Tommasino M. HPV and head and neck cancers: Towards early diagnosis and prevention. Tumour Virus Res 2022; 14:200245. [PMID: 35973657 PMCID: PMC9420391 DOI: 10.1016/j.tvr.2022.200245] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/29/2022] [Accepted: 08/08/2022] [Indexed: 01/13/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with an increasing trend of its incidence. Alcohol consumption, smoking, and viral infections, such as the mucosal high-risk (HR) human papillomaviruses (HPVs) are major risk factors for HNSCC development. In particular, HR HPVs are mainly associated with a subset of oropharyngeal squamous cell carcinoma (OPSCC), while other head and neck sites are marginally affected by HPV infection. HPV16 is the most frequently HR HPV type associated with HNSCC. In contrast to the cervix, no screening programs or identifiable pre-malignant lesions have been characterized for HPV-related HNSCC. Therefore, identification of general diagnostic algorithms and HPV biomarkers that could facilitate the early diagnosis, disease evolution and recurrence for HPV-driven HNSCCs are urgently needed. We herein review the role of HPV in HNSCC with a focus on epidemiology, biology, applied diagnostic algorithms and available biomarkers in body fluids as early diagnostic tools in HPV-driven HNSCCs.
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Affiliation(s)
- Luisa Galati
- International Agency for Research on Cancer, F-69372, Lyon, France
| | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Daria Duca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Marta Tagliabue
- Department of Otolaryngology and Head and Neck Surgery, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy; Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Cindy Simoens
- Unit of Cancer Epidemiology/Belgian Cancer Centre, Sciensano, 1050, Brussels, Belgium
| | - Tarik Gheit
- International Agency for Research on Cancer, F-69372, Lyon, France.
| | - Marc Arbyn
- Unit of Cancer Epidemiology/Belgian Cancer Centre, Sciensano, 1050, Brussels, Belgium; Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, University Ghent, Ghent, Belgium
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4
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Gormley M, Dudding T, Kachuri L, Burrows K, Chong AHW, Martin RM, Thomas SJ, Tyrrell J, Ness AR, Brennan P, Munafò MR, Pring M, Boccia S, Olshan AF, Diergaarde B, Hung RJ, Liu G, Tajara EH, Severino P, Toporcov TN, Lacko M, Waterboer T, Brenner N, Smith GD, Vincent EE, Richmond RC. Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization. BMC Med 2022; 20:40. [PMID: 35094705 PMCID: PMC8802428 DOI: 10.1186/s12916-022-02233-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 01/04/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.
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Affiliation(s)
- Mark Gormley
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
- Bristol Dental Hospital and School, University of Bristol, Bristol, UK.
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
| | - Tom Dudding
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Bristol Dental Hospital and School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Linda Kachuri
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, USA
| | - Kimberley Burrows
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Amanda H W Chong
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Richard M Martin
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- University Hospitals Bristol and Weston NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
| | - Steven J Thomas
- Bristol Dental Hospital and School, University of Bristol, Bristol, UK
- University Hospitals Bristol and Weston NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
| | - Jessica Tyrrell
- University of Exeter Medical School, RILD Building, RD&E Hospital, Exeter, UK
| | - Andrew R Ness
- University Hospitals Bristol and Weston NHS Foundation Trust National Institute for Health Research Bristol Biomedical Research Centre, University of Bristol, Bristol, UK
| | - Paul Brennan
- Genetic Epidemiology Group, World Health Organization, International Agency for Research on Cancer, Lyon, France
| | - Marcus R Munafò
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- School of Psychological Science, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Miranda Pring
- Bristol Dental Hospital and School, University of Bristol, Bristol, UK
| | - Stefania Boccia
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italia
- Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Andrew F Olshan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, USA
| | - Brenda Diergaarde
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, and UPMC Hillman Cancer Center, Pittsburgh, USA
| | - Rayjean J Hung
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Geoffrey Liu
- Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Princess Margaret Cancer Centre, Toronto, Canada
| | - Eloiza H Tajara
- Department of Molecular Biology, School of Medicine of São José do Rio Preto, São Paulo, Brazil
| | - Patricia Severino
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Tatiana N Toporcov
- Department of Epidemiology, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Martin Lacko
- Department of Otorhinolaryngology and Head and Neck Surgery, Research Institute GROW, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Tim Waterboer
- Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - Nicole Brenner
- Infections and Cancer Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
| | - George Davey Smith
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Emma E Vincent
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Rebecca C Richmond
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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5
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Huang CC, Su YC, Chang CC, Lee WT, Ou CY, Wu YH, Wu SY, Lai YH, Huang JS, Chen KC, Hsueh WT, Tsai ST, Yen CJ, Chang JY, Tsai ML, Lin CL, Weng YL, Yang HC, Chen YS, Hsiao JR, Chang JS. Investigating the association between serum human papillomavirus type 16 E7 antibodies and risk of head and neck cancer. Cancer Med 2021; 10:4075-4086. [PMID: 33949155 PMCID: PMC8209620 DOI: 10.1002/cam4.3944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/07/2021] [Accepted: 04/16/2021] [Indexed: 11/15/2022] Open
Abstract
Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital‐based case–control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non‐OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV‐positive OPC. The current study found a a positive association between seropositivity to HPV16 E7 and oropharyngeal cancer risk. This study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan.
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Affiliation(s)
- Cheng-Chih Huang
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Chu Su
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Clinical Medicine Research Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Chan-Chi Chang
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Ting Lee
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chun-Yen Ou
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yuan-Hua Wu
- Department of Radiation Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Shang-Yin Wu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Hsuan Lai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Radiation Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Jehn-Shyun Huang
- Department of Stomatology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Ken-Chung Chen
- Department of Stomatology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Wei-Ting Hsueh
- Department of Radiation Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Sen-Tien Tsai
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Jui Yen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Jang-Yang Chang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli, Taiwan
| | - Mei-Ling Tsai
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Chen-Lin Lin
- Department of Nursing, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Ya-Ling Weng
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Han-Chien Yang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Yu-Shan Chen
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
| | - Jenn-Ren Hsiao
- Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jeffrey S Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
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6
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Balachandra S, Kusin SB, Lee R, Blackwell JM, Tiro JA, Cowell LG, Chiang CM, Wu SY, Varma S, Rivera EL, Mayo HG, Ding L, Sumer BD, Lea JS, Bagrodia A, Farkas LM, Wang R, Fakhry C, Dahlstrom KR, Sturgis EM, Day AT. Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis. Cancer 2021; 127:850-864. [PMID: 33270909 PMCID: PMC8135101 DOI: 10.1002/cncr.33221] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/06/2020] [Accepted: 06/14/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. METHODS Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. RESULTS One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. CONCLUSIONS HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.
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Affiliation(s)
| | | | - Rebecca Lee
- Department of Otolaryngology–Head and Neck Surgery, UT Southwestern Medical Center, Dallas, Texas
| | | | - Jasmin A. Tiro
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
| | - Lindsay G. Cowell
- Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, Texas
- Department of Immunology, UT Southwestern Medical Center, Dallas, Texas
| | - Cheng-Ming Chiang
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas
- Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas
| | - Shwu-Yuan Wu
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas
| | - Sanskriti Varma
- Department of Internal Medicine, NewYork-Presbyterian Hospital–Columbia Campus, New York, New York
| | - Erika L. Rivera
- Department of General Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Helen G. Mayo
- Digital Library and Learning Center, UT Southwestern Medical Center, Dallas, Texas
| | - Lianghao Ding
- Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas
| | - Baran D. Sumer
- Department of Otolaryngology–Head and Neck Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Jayanthi S. Lea
- Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, Texas
| | - Aditya Bagrodia
- Department of Urology, UT Southwestern Medical Center, Dallas, Texas
| | - Linda M. Farkas
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Richard Wang
- Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas
| | - Carole Fakhry
- Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kristina R. Dahlstrom
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Erich M. Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrew T. Day
- Department of Otolaryngology–Head and Neck Surgery, UT Southwestern Medical Center, Dallas, Texas
- Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas
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7
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Dong Z, Hu R, Du Y, Tan L, Li L, Du J, Bai L, Ma Y, Cui H. Immunodiagnosis and Immunotherapeutics Based on Human Papillomavirus for HPV-Induced Cancers. Front Immunol 2021; 11:586796. [PMID: 33488587 PMCID: PMC7820759 DOI: 10.3389/fimmu.2020.586796] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/24/2020] [Indexed: 12/27/2022] Open
Abstract
Infection with human papillomavirus (HPV) is one of the main causes of malignant neoplasms, especially cervical, anogenital, and oropharyngeal cancers. Although we have developed preventive vaccines that can protect from HPV infection, there are still many new cases of HPV-related cancers worldwide. Early diagnosis and therapy are therefore important for the treatment of these diseases. As HPVs are the major contributors to these cancers, it is reasonable to develop reagents, kits, or devices to detect and eliminate HPVs for early diagnosis and therapeutics. Immunological methods are precise strategies that are promising for the accurate detection and blockade of HPVs. During the last decades, the mechanism of how HPVs induce neoplasms has been extensively elucidated, and several oncogenic HPV early proteins, including E5, E6, and E7, have been shown to be positively related to the oncogenesis and malignancy of HPV-induced cancers. These oncoproteins are promising biomarkers for diagnosis and as targets for the therapeutics of HPV-related cancers. Importantly, many specific monoclonal antibodies (mAbs), or newly designed antibody mimics, as well as new immunological kits, devices, and reagents have been developed for both the immunodiagnosis and immunotherapeutics of HPV-induced cancers. In the current review, we summarize the research progress in the immunodiagnosis and immunotherapeutics based on HPV for HPV-induced cancers. In particular, we depict the most promising serological methods for the detection of HPV infection and several therapeutical immunotherapeutics based on HPV, using immunological tools, including native mAbs, radio-labelled mAbs, affitoxins (affibody-linked toxins), intracellular single-chain antibodies (scFvs), nanobodies, therapeutical vaccines, and T-cell-based therapies. Our review aims to provide new clues for researchers to develop novel strategies and methods for the diagnosis and treatment of HPV-induced tumors.
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Affiliation(s)
- Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, China.,NHC Key Laboratory of Birth Defects and Reproductive Health (Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute), Chongqing, China
| | - Renjian Hu
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Yan Du
- Department of Ultrasound, Chongqing University Central Hospital (Chongqing Emergency Medical Center), Chongqing, China
| | - Li Tan
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Lin Li
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, China.,Department of Immunology, School of Basic Medicine, Southwest Medical University, Luzhou, China
| | - Juan Du
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Longchang Bai
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Yingkang Ma
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.,Cancer Center, Reproductive Medicine Center, Medical Research Institute, Southwest University, Chongqing, China.,NHC Key Laboratory of Birth Defects and Reproductive Health (Chongqing Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute), Chongqing, China
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8
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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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9
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von Witzleben A, Wang C, Laban S, Savelyeva N, Ottensmeier CH. HNSCC: Tumour Antigens and Their Targeting by Immunotherapy. Cells 2020; 9:E2103. [PMID: 32942747 PMCID: PMC7564543 DOI: 10.3390/cells9092103] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/09/2020] [Accepted: 09/13/2020] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials.
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Affiliation(s)
- Adrian von Witzleben
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; (A.v.W.); (N.S.)
- Department of Otorhinolaryngology, Head & Neck Surgery, University of Ulm, 89081 Ulm, Germany;
| | - Chuan Wang
- Head and Neck Center, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZX, UK;
| | - Simon Laban
- Department of Otorhinolaryngology, Head & Neck Surgery, University of Ulm, 89081 Ulm, Germany;
| | - Natalia Savelyeva
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; (A.v.W.); (N.S.)
| | - Christian H. Ottensmeier
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK; (A.v.W.); (N.S.)
- Head and Neck Center, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZX, UK;
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10
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Broglie Däppen MA. [Update for Diagnosis and Management of HPV-Driven Oropharyngeal Cancer]. PRAXIS 2020; 109:697-703. [PMID: 32635845 DOI: 10.1024/1661-8157/a003484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Update for Diagnosis and Management of HPV-Driven Oropharyngeal Cancer Abstract. In the past decades, an increasing incidence of oropharyngeal squamous cell cancer could be observed. More than twenty years ago, a correlation between a pharyngeal Human papillomavirus high-risk type infection and the development of oropharyngeal cancer has been suspected. Especially younger patients without the former risk factors smoking and alcohol have a higher prevalence for this cancer type. HPV-associated cancer is developing in the lymphatic tissue of the tonsils and the base of the tongue. HPV-driven tumors can be defined as a clinical and morphologic distinct tumor entity with a significantly better prognosis compared to tumors based on smoking and alcohol consumption. They are demonstrating a clearly better treatment response irrespective of the treatment modality. The tumor development is assumed to be comparable to cervical cancer, probably through a step-wise process from dysplasia to invasive cancer. In the pharynx, no HPV-associated precursor lesions have been detected so far. Therefore, Screening program proven to be very successful in the cervix have not could not have been implemented so far. The reduction of HPV-associated tumor burden in the cervix is likely to be compensated by the rising number of HPV-driven oropharyngeal cancer. P16 as a surrogate marker for HPV has been implemented in the 8th edition of the TNM classification for oropharyngeal cancer. A worldwide accepted definition of an HPV-driven tumor is lacking so far. P16 immunhistochemistry or HPV-DNA detection by PCR as single markers have an insufficient sensitivity and specificity. A combination of both markers demonstrates a higher accuracy compared to the gold standard RNA. Antibodies to HPV oncoproteins are reliable diagnostic and prognostic markers that could in the future possibly serve for early tumor detection.
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11
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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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12
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Albano PM, Salvador C, Orosa J, Racelis S, Leaño M, Michel A, Ramos JD, Holzinger D, Pawlita M. Human Papillomavirus Serologic Profiles of Selected Filipinos with Head and Neck Squamous Cell Carcinoma. J Pathol Transl Med 2019; 53:273-279. [PMID: 31142100 PMCID: PMC6755648 DOI: 10.4132/jptm.2019.05.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 05/12/2019] [Indexed: 11/17/2022] Open
Abstract
Background The low prevalence of human papillomavirus (HPV) DNA and mRNA in biopsy samples of Filipinos with head and neck squamous cell carcinoma (HNSCC) has been reported previously. Here, the HPV serologic profiles of HNSCC cases were analyzed and associated with lifestyle and sexual practices. Methods Serum samples were collected between May 2012 and September 2013 from HNSCC patients (n = 22) in the northwest region of the Philippines, and age- and sex-matched clinically healthy controls. Antibodies to capsid and early oncoproteins of HPV16, 18, 31, 33, 45, 52, 58, 6, and 11 were analyzed using multiplex serology. Results Most of the cases were males with tumors of the oral cavity or larynx. Two of the cases tested positive for at least one of the early oncoproteins (E6, E7, E1, and/or E2) of HPV16, and 11 did not display reactivity to any HPV early or late oncoproteins. Of the controls, four tested positive for at least one of the HPV16 early oncoproteins, and 10 were non-reactive to all HPV types. Titers to HPV16 E6 or E7 of the seropositive cases and controls were considerably lower than those typically observed in economically developed countries. Conclusions The low HPV titers seen here are consistent with the results of molecular analyses for this population. Hence, the seropositivity of some of the HNSCC cases is likely an indication of prior exposure to the virus and not the presence of HPV-driven tumors.
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Affiliation(s)
- Pia Marie Albano
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Biology, College of Science, University of Santo Tomas, Manila, Philippines.,Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines
| | - Christianne Salvador
- Department of ENT Head and Neck Surgery, Mariano Marcos Memorial Hospital and Medical Center, Ilocos Norte, Philippines
| | - Jose Orosa
- Department of ENT Head and Neck Surgery, Mariano Marcos Memorial Hospital and Medical Center, Ilocos Norte, Philippines
| | - Sheryl Racelis
- Department of Pathology and Laboratories, Mariano Marcos Memorial Hospital and Medical Center, Ilocos Norte, Philippines
| | - Modesty Leaño
- Department of Pathology and Laboratories, Mariano Marcos Memorial Hospital and Medical Center, Ilocos Norte, Philippines
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - John Donnie Ramos
- Department of Biology, College of Science, University of Santo Tomas, Manila, Philippines.,Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila, Philippines
| | - Dana Holzinger
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
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13
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Wang HF, Wang SS, Tang YJ, Chen Y, Zheng M, Tang YL, Liang XH. The Double-Edged Sword-How Human Papillomaviruses Interact With Immunity in Head and Neck Cancer. Front Immunol 2019; 10:653. [PMID: 31001266 PMCID: PMC6454067 DOI: 10.3389/fimmu.2019.00653] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/11/2019] [Indexed: 02/05/2023] Open
Abstract
Patients with human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have remarkably better prognosis, which differs from HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) with respect to clinical, genomic, molecular, and immunological aspects, especially having the characteristics of high levels of immune cell infiltration and high degrees of immunosuppression. This review will summarize immune evasion mechanisms in HPV-positive HNSCC, analyze the host various immune responses to HPV and abundant numbers of infiltrating immune cell, and discuss the differences between HPV-positive HNSCC with cervical cancer. A deeper understanding of the immune landscape will help new concepts to emerge in immune-checkpoint oncology, which might be a valuable add-on to established concepts.
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Affiliation(s)
- Hao-Fan Wang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Sha-Sha Wang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Ya-Jie Tang
- Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan, China
| | - Yu Chen
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Min Zheng
- Department of Stomatology, Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China
| | - Ya-Ling Tang
- State Key Laboratory of Oral Diseases, Department of Oral Pathology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
| | - Xin-Hua Liang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology (Sichuan University), Chengdu, China
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14
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Beynon RA, Lang S, Schimansky S, Penfold CM, Waylen A, Thomas SJ, Pawlita M, Tim Waterboer, Martin RM, May M, Ness AR. Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all-cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer. Int J Cancer 2018; 143:1114-1127. [PMID: 29607493 PMCID: PMC6099366 DOI: 10.1002/ijc.31416] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 02/16/2018] [Accepted: 03/13/2018] [Indexed: 12/12/2022]
Abstract
Tobacco smoking and alcohol consumption are well-established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all-cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully-adjusted HR for current versus never-smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non-drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all-cause mortality in models adjusted for important prognostic factors.
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Affiliation(s)
- Rhona A. Beynon
- Population Health SciencesBristol Medical School, University of Bristol, Canynge HallBristolBS8 2PSUnited Kingdom
- MRC Integrative Epidemiology Unit (IEU)BristolBS8 2BNUnited Kingdom
| | - Samantha Lang
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
| | - Sarah Schimansky
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
| | - Christopher M. Penfold
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
| | - Andrea Waylen
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
- School of Oral and Dental Sciences, University of BristolBS1 2LYUnited Kingdom
| | - Steven J. Thomas
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
- School of Oral and Dental Sciences, University of BristolBS1 2LYUnited Kingdom
| | - Michael Pawlita
- Molecular Diagnostics of Oncogenic Infections DivisionGerman Cancer Research Center (DKFZ), Im Neuenheimer Feld 280Heidelberg69120Germany
| | - Tim Waterboer
- Molecular Diagnostics of Oncogenic Infections DivisionGerman Cancer Research Center (DKFZ), Im Neuenheimer Feld 280Heidelberg69120Germany
- Infections and Cancer EpidemiologyGerman Cancer Research Center (DKFZ), Im Neuenheimer Feld 280Heidelberg69120Germany
| | - Richard M. Martin
- Population Health SciencesBristol Medical School, University of Bristol, Canynge HallBristolBS8 2PSUnited Kingdom
- MRC Integrative Epidemiology Unit (IEU)BristolBS8 2BNUnited Kingdom
| | - Margaret May
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
| | - Andy R. Ness
- National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
- School of Oral and Dental Sciences, University of BristolBS1 2LYUnited Kingdom
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15
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Huang CG, Lee LA, Liao CT, Yen TC, Yang SL, Liu YC, Li JC, Gong YN, Kang CJ, Huang SF, Fang KH, Chang KP, Lee LY, Hsueh C, Shih SR, Tsao KC. Molecular and serologic markers of HPV 16 infection are associated with local recurrence in patients with oral cavity squamous cell carcinoma. Oncotarget 2018; 8:34820-34835. [PMID: 28422732 PMCID: PMC5471014 DOI: 10.18632/oncotarget.16747] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 03/20/2017] [Indexed: 01/11/2023] Open
Abstract
Human papillomavirus (HPV) infections predict mortality in Taiwanese patients with oral cavity squamous cell carcinoma (OCSCC). To address their prognostic significance for local recurrence (LR), in this retrospective cohort study we investigated different serologic and molecular markers of HPV 16 infection in 85 consecutive patients with primary OCSCC who received standard treatment and had their sera stored before treatment. Resected tumor specimens were examined with PCR-based assays for HPV 16 E6/E7 mRNA expression. Sera were tested with suspension arrays for the presence of HPV-specific antibodies using synthetic L1 and E6 peptides as well as a synthetic E7 protein. HPV 16 E6/E7 mRNA, anti-L1, anti-E6, and anti-E7 antibodies tested positive in 12%, 25%, 38%, and 41% of the study patients, respectively. Multivariate analysis identified pathological T3/T4, E6/E7 mRNA, and anti-E7 antibodies as independent risk factors for LR, whereas anti-E6 antibodies were an independent protective factor. In patients with ≥ 3 (high-risk group), 2 (intermediate-risk), and ≤ 1 (low-risk) independent risk factors (predictors), the 5-year LR rates were 75%, 42%, and 4%, respectively. Results were validated in an independent cohort. Together, our preliminary data indicate that HPV 16 infections as well as low and high serum levels of anti-E6 and anti-E7 antibodies, respectively, can serve as biomarkers of LR in patients with OCSCC, whereas the clinical usefulness of anti-HPV 16 antibodies for risk stratification of newly diagnosed cases deserves further scrutiny.
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Affiliation(s)
- Chung-Guei Huang
- Department of Laboratory Medicine, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.,Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, ROC.,Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Li-Ang Lee
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Chun-Ta Liao
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Tzu-Chen Yen
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Molecular Imaging Center, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Shu-Li Yang
- Department of Laboratory Medicine, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.,Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Yi-Chun Liu
- Department of Laboratory Medicine, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Jung-Chin Li
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Yu-Nong Gong
- Department of Laboratory Medicine, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Chung-Jan Kang
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Shiang-Fu Huang
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Ku-Hao Fang
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Kai-Ping Chang
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Li-Yu Lee
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Pathology, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Chuen Hsueh
- Faculty of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Department of Pathology, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC
| | - Shin-Ru Shih
- Department of Laboratory Medicine, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.,Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, ROC.,Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Kuo-Chien Tsao
- Department of Laboratory Medicine, Head and Neck Oncology Group, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan, ROC.,Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, ROC
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16
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Shah A, Malik A, Garg A, Mair M, Nair S, Chaturvedi P. Oral sex and human papilloma virus-related head and neck squamous cell cancer: a review of the literature. Postgrad Med J 2017; 93:704-709. [PMID: 28778951 DOI: 10.1136/postgradmedj-2016-134603] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 04/30/2017] [Accepted: 06/26/2017] [Indexed: 01/12/2023]
Abstract
Head neck squamous cell carcinomas (HNSCCs) are a significant cause of morbidity and mortality all around the world. Just like tobacco and alcohol, Human papilloma virus (HPV) infection is now recognized to play a role in the pathogenesis of a subset of HNSCCs. Unprotected sexual behaviours with the HPV carrier plays an important role in transmission of this virus. The global incidence of head and neck cancers is declining, but the incidence of HPV related head and neck cancers is rapidly increasing over the last few decades. However, most institutions do not mandate documentation of sexual history or counselling of patients regarding sexual practices like they do for tobacco and alcohol addictions in HNSCC patients. The aim of this review of literature is to analyse if there is a strong evidence to correlate oral sex with HPV related HNSCC and counsel the patient's regarding sexual behaviours.
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Affiliation(s)
- Ankit Shah
- Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, India
| | - Akshat Malik
- Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, India
| | - Apurva Garg
- Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, India
| | - Manish Mair
- Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, India
| | - Sudhir Nair
- Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, India
| | - Pankaj Chaturvedi
- Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, India
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17
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Hanna GJ, Sridharan V, Margalit DN, La Follette SK, Chau NG, Rabinowits G, Lorch JH, Haddad RI, Tishler RB, Anderson KS, Schoenfeld JD. Salivary and serum HPV antibody levels before and after definitive treatment in patients with oropharyngeal squamous cell carcinoma. Cancer Biomark 2017; 19:129-136. [DOI: 10.3233/cbm-160071] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Glenn J. Hanna
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Danielle N. Margalit
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, Boston, MA, USA
| | - Stephanie K. La Follette
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, Boston, MA, USA
| | - Nicole G. Chau
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Jochen H. Lorch
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Robert I. Haddad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Roy B. Tishler
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, Boston, MA, USA
| | - Karen S. Anderson
- School of Life Sciences, Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Jonathan D. Schoenfeld
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, Boston, MA, USA
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18
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Broglie MA, Jochum W, Michel A, Waterboer T, Foerbs D, Schoenegg R, Stoeckli SJ, Pawlita M, Holzinger D. Evaluation of type-specific antibodies to high risk-human papillomavirus (HPV) proteins in patients with oropharyngeal cancer. Oral Oncol 2017. [PMID: 28622890 DOI: 10.1016/j.oraloncology.2017.05.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES High risk human papillomavirus (HR-HPV) infection leads to a subgroup of oropharyngeal cancer (OPSCC) characterized by improved treatment response. However an universally accepted definition of an HR-HPV-attributable cancer is lacking. METHODS Detailed, type-specific HPV antibody responses were analyzed by multiplex serology in HR-HPV-attributable OPSCC patients, defined by p16INK4A overexpression and HR-HPV DNA detection by PCR amplification and sequencing. RESULTS Fifty patients were prospectively enrolled. 26/50 (52%) tumor samples were positive for both p16INK4A expression and HR-HPV DNA (22 HPV16, 4 HPV33). Seropositivity was present in 26/26 HPV-attributable OPSCC and one p16INK4A-positive/HPV DNA-negative case. The sensitivity and specificity to diagnose an HR-HPV-attributable tumor was 100% and 96%, respectively for anti-E6 reactivity, 82% and 100%, respectively for anti-E2 reactivity, and clearly lower for anti-E7, anti-E1, anti-E4 and anti-L1-reactivity. 3yr-overall (OS) and disease specific survival (DSS) was higher in patients with HR-HPV-attributable tumors (OS 88% vs 64%, p=0.02; DSS 90% vs 80%, p=0.07) and seropositive patients (OS 88% vs 62%, p=0.01; DSS 92% vs 78%, p=0.05) than HR-HPV-negative or seronegative patients. CONCLUSIONS Detection of HR-HPV type-specific antibodies highly correlated with HPV-attributable OPSCC and was associated with better survival. HR-HPV antibodies are promising diagnostic, prognostic and potentially screening markers in HR-HPV-attributable OPSCC.
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Affiliation(s)
- Martina A Broglie
- Department of Otorhinolaryngology, Head and Neck Surgery, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
| | - Wolfram Jochum
- Institute of Pathology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infections, Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infections, Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Diana Foerbs
- Institute of Pathology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
| | - René Schoenegg
- Institute of Pathology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
| | - Sandro J Stoeckli
- Department of Otorhinolaryngology, Head and Neck Surgery, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infections, Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Dana Holzinger
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infections, Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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19
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Holzinger D, Wichmann G, Baboci L, Michel A, Höfler D, Wiesenfarth M, Schroeder L, Boscolo‐Rizzo P, Herold‐Mende C, Dyckhoff G, Boehm A, Del Mistro A, Bosch FX, Dietz A, Pawlita M, Waterboer T. Sensitivity and specificity of antibodies against HPV16 E6 and other early proteins for the detection of HPV16‐driven oropharyngeal squamous cell carcinoma. Int J Cancer 2017; 140:2748-2757. [DOI: 10.1002/ijc.30697] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/21/2017] [Accepted: 02/27/2017] [Indexed: 01/12/2023]
Affiliation(s)
- Dana Holzinger
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
| | - Gunnar Wichmann
- Department of OtorhinolaryngologyUniversity Hospital LeipzigLeipzig Germany
| | - Lorena Baboci
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
- Department of Oncology and Surgical SciencesUniversity of PaduaPadua Italy
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
| | - Daniela Höfler
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
| | - Manuel Wiesenfarth
- Division of BiostatisticsGerman Cancer Research CenterHeidelberg Germany
| | - Lea Schroeder
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
| | - Paolo Boscolo‐Rizzo
- Department of NeurosciencesENT Clinic and Regional Center for Head and Neck Cancer, University of PaduaTreviso Italy
| | - Christel Herold‐Mende
- Department of Otorhinolaryngology, Head and Neck SurgeryHeidelberg UniversityHeidelberg Germany
- Department of Neurosurgery, Division of Experimental NeurosurgeryHeidelberg UniversityHeidelberg Germany
| | - Gerhard Dyckhoff
- Department of Otorhinolaryngology, Head and Neck SurgeryHeidelberg UniversityHeidelberg Germany
| | - Andreas Boehm
- Department of OtorhinolaryngologyUniversity Hospital LeipzigLeipzig Germany
| | - Annarosa Del Mistro
- Department of Immunology and Molecular OncologyIRCCS Veneto Institute of Oncology (IOV)Padua Italy
| | - Franz X. Bosch
- Department of Otorhinolaryngology, Head and Neck SurgeryHeidelberg UniversityHeidelberg Germany
| | - Andreas Dietz
- Department of OtorhinolaryngologyUniversity Hospital LeipzigLeipzig Germany
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer ProgramGerman Cancer Research Center (DKFZ)Heidelberg Germany
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20
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Perdomo S, Martin Roa G, Brennan P, Forman D, Sierra MS. Head and neck cancer burden and preventive measures in Central and South America. Cancer Epidemiol 2016; 44 Suppl 1:S43-S52. [PMID: 27678322 DOI: 10.1016/j.canep.2016.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 03/14/2016] [Accepted: 03/21/2016] [Indexed: 01/01/2023]
Abstract
RATIONALE AND OBJECTIVE Central and South America comprise one of the areas characterized by high incidence rates for head and neck cancer. We describe the geographical and temporal trends in incidence and mortality of head and neck cancers in the Central and South American region in order to identify opportunities for intervention on the major identified risk factors: tobacco control, alcohol use and viral infections. METHODS We obtained regional- and national-level incidence data from 48 population-based cancer registries in 13 countries and cancer deaths from the WHO mortality database for 18 countries. Age-standardized incidence (ASR) and mortality (ASMR) rates per 100,000 person-years were estimated. RESULTS Brazil had the highest incidence rates for oral and pharyngeal cancer in the region for both sexes, followed by Cuba, Uruguay and Argentina. Cuba had the highest incidence and mortality rates of laryngeal cancer in the region for males and females. Overall, males had rates about four times higher than those in females. Most countries in the region have implemented WHO recommendations for both tobacco and alcohol public policy control. CONCLUSION Head and neck squamous-cell cancer (HNSCC) incidence and mortality rates in the Central and South America region vary considerably across countries, with Brazil, Cuba, French Guyana, Uruguay and Argentina experiencing the highest rates in the region. Males carry most of the HNSCC burden. Improvement and implementation of comprehensive tobacco and alcohol control policies as well as the monitoring of these factors are fundamental to prevention of head and neck cancers in the region.
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Affiliation(s)
- Sandra Perdomo
- International Agency for Research on Cancer, Section of Genetics, France.
| | | | - Paul Brennan
- International Agency for Research on Cancer, Section of Genetics, France
| | - David Forman
- International Agency for Research on Cancer, Section of Cancer Surveillance, France
| | - Mónica S Sierra
- International Agency for Research on Cancer, Section of Cancer Surveillance, France
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21
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Zhang Y, Waterboer T, Pawlita M, Sugar E, Minkoff H, Cranston RD, Wiley D, Burk R, Reddy S, Margolick J, Strickler H, Weber K, Gillison M, D'Souza G. Human Papillomavirus (HPV) 16 E6 seropositivity is elevated in subjects with oral HPV16 infection. Cancer Epidemiol 2016; 43:30-4. [PMID: 27344614 DOI: 10.1016/j.canep.2016.06.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/13/2016] [Accepted: 06/15/2016] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Human Papillomavirus (HPV) 16 E6 serum antibodies are common in people with HPV-related oropharyngeal cancers (HPV-OPC), but not the general population. We explored HPV16 seroprevalence in people with and without oral HPV16 infection, the cause of HPV-OPC. METHODS Oral rinse samples were collected semiannually and tested for 36 types of HPV DNA by PCR. HPV16 E6 serum antibodies were tested at the visit of first oral HPV detection in participants with prevalent (n=54), or incident (n=39) oral HPV16 DNA; or at baseline in matched participants with no oral HPV16 DNA (n=155) using multiplex serology assay. Predictors of seropositivity were examined using logistic regression. RESULTS HPV16 E6 seropositivity (7.5% vs 0.7%; p=0.005) but not seropositivity to the other HPV16 antigens, was significantly more common in those with than without oral HPV16 infection. There were only 8 HPV16 E6 seropositive participants, but oral HPV16 DNA remained a strong predictor of E6 seropositivity after adjustment for other risk factors (aOR=14.6 95%CI, 1.7-122.5). Seroprevalence was similar in those with prevalent (7.4%; 4/54), and incident (7.7%; 3/39) oral HPV16 infection (p=1.00). E6 seroprevalence was associated with reduced oral HPV16 clearance, but was not statistically significant (HR=0.65 95% CI, 0.16-2.70). Seropositive participants were primarily male (87.5%), HIV-positive (75.0%; median CD4 cell-count of 840) and had oral HPV16 DNA (87.5%). History of an HPV-related cancer (0/8) or HPV-related anogenital dysplasia (1/8) was rare, and 4 participants had recent screening showing no anogenital dysplasia. DISCUSSION HPV16 E6 seropositivity was higher among people with than without oral HPV16 infection, despite no known anogenital disease in these participants.
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Affiliation(s)
- Yuehan Zhang
- Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD 21205, United States
| | - Tim Waterboer
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Michael Pawlita
- German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Elizabeth Sugar
- Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD 21205, United States
| | - Howard Minkoff
- Maimonides Medical Center, 4802 Tenth Avenue, Brooklyn, NY 11219, United States
| | - Ross D Cranston
- University of Pittsburgh, 3520 Fifth Avenue, Pittsburgh, PA 15213, United States
| | - Dorothy Wiley
- University of California, Los Angeles, 2-256 Factor Bldg., Los Angeles, CA 90095-1702, United States
| | - Robert Burk
- Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, United States
| | - Susheel Reddy
- Northwestern University, 645 N Michigan Ave., Chicago, IL 60611, United States
| | - Joseph Margolick
- Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD 21205, United States
| | - Howard Strickler
- Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, United States
| | - Kathleen Weber
- CORE Center at John H. Stroger Jr. Hospital of Cook County, 2225 W Harrison St., Chicago, IL 60612, United States
| | - Maura Gillison
- Ohio State University Comprehensive Cancer Center, 420 W 12th Ave., Columbus, OH 43210, United States
| | - Gypsyamber D'Souza
- Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St., Baltimore, MD 21205, United States.
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22
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Anantharaman D, Muller DC, Lagiou P, Ahrens W, Holcátová I, Merletti F, Kjærheim K, Polesel J, Simonato L, Canova C, Castellsague X, Macfarlane TV, Znaor A, Thomson P, Robinson M, Conway DI, Healy CM, Tjønneland A, Westin U, Ekström J, Chang-Claude J, Kaaks R, Overvad K, Drogan D, Hallmans G, Laurell G, Bueno-de-Mesquita HB, Peeters PH, Agudo A, Larrañaga N, Travis RC, Palli D, Barricarte A, Trichopoulou A, George S, Trichopoulos D, Quirós JR, Grioni S, Sacerdote C, Navarro C, Sánchez MJ, Tumino R, Severi G, Boutron-Ruault MC, Clavel-Chapelon F, Panico S, Weiderpass E, Lund E, Gram IT, Riboli E, Pawlita M, Waterboer T, Kreimer AR, Johansson M, Brennan P. Combined effects of smoking and HPV16 in oropharyngeal cancer. Int J Epidemiol 2016; 45:752-61. [PMID: 27197530 PMCID: PMC5841602 DOI: 10.1093/ije/dyw069] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/05/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood. METHODS Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression. RESULTS Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer. CONCLUSIONS Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.
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Affiliation(s)
- Devasena Anantharaman
- Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - David C Muller
- Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Wolfgang Ahrens
- Leibniz Institute for Prevention Research and Epidemiology, BIPS, Bremen, Germany, Faculty of Mathematics and Computer Science, University of Bremen, Bremen, Germany
| | - Ivana Holcátová
- Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University of Prague, Prague, Czech Republic
| | - Franco Merletti
- Unit of Cancer Epidemiology, Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Jerry Polesel
- Unit of Epidemiology and Biostatistics, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Lorenzo Simonato
- Laboratory of Public Health and Population Studies, Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Cristina Canova
- Laboratory of Public Health and Population Studies, Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Xavier Castellsague
- Unit of Infections and Cancer, Institut Català d'Oncologia (ICO), IDIBELL, CIBERESP, L'Hospitalet de Llobregat, Barcelona, Spain
| | | | - Ariana Znaor
- Croatian National Cancer Registry, Croatian National Institute of Public Health, Zagreb, Croatia, Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France
| | - Peter Thomson
- Centre for Oral Health Research, Newcastle University, Newcastle-upon-Tyne, UK
| | - Max Robinson
- Centre for Oral Health Research, Newcastle University, Newcastle-upon-Tyne, UK
| | - David I Conway
- Dental School, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Claire M Healy
- School of Dental Science, Trinity College Dublin, Dublin, Ireland
| | - Anne Tjønneland
- Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark
| | - Ulla Westin
- Department of Otorhinolaryngology of Malmö and Lund
| | - Johanna Ekström
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | | | - Dagmar Drogan
- German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Nuthetal, Germany
| | - Göran Hallmans
- Department of Biobank Research, Umeå University, Umeå, Sweden
| | - Göran Laurell
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - H B Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands, Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands, Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK, Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Petra H Peeters
- Department of Epidemiology, Julius Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht, The Netherlands, MRC-PHE, Imperial College London, School of Public Health, London, UK
| | - Antonio Agudo
- Unit of Nutrition and Cancer, Institut Català d'Oncologia (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Nerea Larrañaga
- Public Health Division of Gipuzkoa, BIODonostia Research Institute, Basque Health Department, San Sebastián, Spain, CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Domenico Palli
- Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Florence, Italy
| | - Aurelio Barricarte
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain, Navarre Public Health Institute, Pamplona, Spain
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece, Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
| | - Saitakis George
- Hellenic Health Foundation, Athens, Greece, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
| | - Dimitrios Trichopoulos
- Hellenic Health Foundation, Athens, Greece, Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | | | - Sara Grioni
- Epidemiology and Prevention Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlotta Sacerdote
- Unit of Cancer Epidemiology, Citta' della Salute e della Scienza Hospital, University of Turin and Centre for Cancer Prevention (CPO), Turin, Italy
| | - Carmen Navarro
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain, Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain, Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
| | - María-José Sánchez
- CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain, Instituto de Investigación Biosanitaria, Universidad de Granada, Granada, Spain
| | - Rosario Tumino
- Cancer Registry and Histopathology Unit, Civic - M P Arezzo Hospital, ASP Ragusa, Ragusa, Italy
| | - Gianluca Severi
- Human Genetics Foundation (HuGeF), Torino, Italy, Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, VIC, Australia
| | - Marie-Christine Boutron-Ruault
- INSERM, Centre for research in Epidemiology and Population Health (CESP), Villejuif, France, Université Paris Sud, Villejuif, France, Institut Gustave Roussy, Villejuif, France
| | - Francoise Clavel-Chapelon
- INSERM, Centre for research in Epidemiology and Population Health (CESP), Villejuif, France, Université Paris Sud, Villejuif, France, Institut Gustave Roussy, Villejuif, France
| | - Salvatore Panico
- Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
| | - Elisabete Weiderpass
- Department of Community Medicine, Faculty of Health Science, University of Tromsø, Arctic University of Norway, Tromsø, Norway, Cancer Registry of Norway, Oslo, Norway, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, Department of Genetic Epidemiology, Folkhälsan Research Centre, Helsinki, Finland
| | - Eiliv Lund
- Department of Community Medicine, Faculty of Health Science, University of Tromsø, Arctic University of Norway, Tromsø, Norway
| | - Inger T Gram
- Department of Community Medicine, Faculty of Health Science, University of Tromsø, Arctic University of Norway, Tromsø, Norway
| | - Elio Riboli
- School of Public Health, Imperial College London, London, UK
| | - Michael Pawlita
- German Cancer Research Centre (DKFZ), Heidelberg, Germany and
| | - Tim Waterboer
- German Cancer Research Centre (DKFZ), Heidelberg, Germany and
| | | | - Mattias Johansson
- Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Paul Brennan
- Genetic Epidemiology Group, International Agency for Research on Cancer, Lyon, France,
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Boscolo-Rizzo P, Pawlita M, Holzinger D. From HPV-positive towards HPV-driven oropharyngeal squamous cell carcinomas. Cancer Treat Rev 2016; 42:24-9. [DOI: 10.1016/j.ctrv.2015.10.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 10/22/2015] [Indexed: 11/15/2022]
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24
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Human papillomavirus E7 serology and association with p16 immunohistochemistry in squamous cell carcinoma of the head and neck. Exp Mol Pathol 2015; 99:335-40. [DOI: 10.1016/j.yexmp.2015.06.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 06/22/2015] [Indexed: 12/14/2022]
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25
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Farsi NJ, El-Zein M, Gaied H, Lee YCA, Hashibe M, Nicolau B, Rousseau MC. Sexual behaviours and head and neck cancer: A systematic review and meta-analysis. Cancer Epidemiol 2015; 39:1036-46. [PMID: 26372414 DOI: 10.1016/j.canep.2015.08.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/06/2015] [Indexed: 01/01/2023]
Abstract
Human papillomaviruses (HPV) are associated with head and neck cancers (H&NC). Transmission of HPV to the upper aerodigestive tract occurs plausibly through sexual contact, although epidemiologic evidence on the role of sexual behaviours in H&NC aetiology is inconsistent. We conducted a meta-analysis of studies examining the association between four indicators of sexual behaviours (number of sexual partners and oral sex partners, oral sex practice, and age at first intercourse) and H&NC. Summary odds ratios (OR) and 95% confidence intervals (CI) were estimated using fixed and random effects models for each indicator, contrasting 'highest' to 'lowest', 'ever' to 'never', or 'youngest' to 'oldest' categories. Twenty case-control studies were included out of 3838 identified publications. Using random effects models, summary ORs suggested an increased risk of H&NC for number of sexual partners [OR=1.29, 95% CI: 1.02-1.63] (19 studies) and number of oral sex partners [OR=1.69, 95% CI: 1.00-2.84] (5 studies), whereas no effect was observed with oral sex practice [OR=1.09, 95% CI: 0.88-1.35] (17 studies) and age at first intercourse [OR=1.40, 95% CI: 0.71-2.79] (6 studies). For number of sexual partners and oral sex practice, which were assessed in more studies, we further excluded studies contributing to heterogeneity and those not adjusted for age, sex, smoking, and alcohol consumption. The summary ORs were 0.95 (95% CI: 0.75-1.20) for number of sexual partners and 1.03 (95% CI: 0.84-1.26) for oral sex practice. Our findings highlight that observed associations might be partly attributed to confounding effects of sociodemographic and behavioural factors.
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Affiliation(s)
- N J Farsi
- Oral Health and Society Division, Faculty of Dentistry, McGill University, Montréal, Québec, Canada; Epidemiology and Biostatistics Unit, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada
| | - M El-Zein
- Epidemiology and Biostatistics Unit, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada
| | - H Gaied
- Oral Health and Society Division, Faculty of Dentistry, McGill University, Montréal, Québec, Canada
| | - Y C A Lee
- Division of Public Health, Department of Family & Preventive Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - M Hashibe
- Division of Public Health, Department of Family & Preventive Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, United States
| | - B Nicolau
- Oral Health and Society Division, Faculty of Dentistry, McGill University, Montréal, Québec, Canada
| | - M-C Rousseau
- Oral Health and Society Division, Faculty of Dentistry, McGill University, Montréal, Québec, Canada; Epidemiology and Biostatistics Unit, INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada.
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26
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Prendes BL, Wang SJ, Groppo ER, Eisele DW, Palefsky JM. Oral human papillomavirus infection in men who have sex with men with anal squamous intraepithelial lesions. Head Neck 2015; 38 Suppl 1:E399-405. [PMID: 25580925 DOI: 10.1002/hed.24006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Little is known about the association between oral and anogenital human papillomavirus (HPV) infections. METHODS Oral and anal samples from 66 men who have sex with men with a history of HPV-related anogenital squamous intraepithelial lesions were analyzed using polymerase chain reaction (PCR), and typed for 38 HPV types. RESULTS Prevalence of oral HPV infection was 30%, versus 82% for anal infection. Prevalence of oral and anal high-risk HPV infection was 11% and 64%, respectively. Concurrent oral-anal any-type HPV infection was found in 26% of participants, whereas concordant type-specific HPV prevalence was 5%. In multivariate analysis, number of partners from whom the participant received oral-penile sex and number of partners on whom the participant performed oral-penile sex were associated with oral HPV infection. CONCLUSION Oral HPV prevalence in this cohort is high, however, concordant type-specific oral-anal HPV infection was rare. Increased risk of oral HPV infection was associated with oral-penile sex. © 2015 Wiley Periodicals, Inc. Head Neck 38: E399-E405, 2016.
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Affiliation(s)
- Brandon L Prendes
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California
| | - Steven J Wang
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California
| | - Eli R Groppo
- Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California
| | - David W Eisele
- Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Joel M Palefsky
- Department of Medicine, University of California, San Francisco, San Francisco, California
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27
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Biologic predictors of serologic responses to HPV in oropharyngeal cancer: The HOTSPOT study. Oral Oncol 2015; 51:751-8. [PMID: 26094591 DOI: 10.1016/j.oraloncology.2015.05.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 05/19/2015] [Accepted: 05/24/2015] [Indexed: 01/11/2023]
Abstract
OBJECTIVES We hypothesized that viral and host factors impact the serologic responses to HPV early antigens in HPV-positive oropharyngeal cancer (HPVOPC). MATERIALS AND METHODS We conducted a multicenter study to measure HPV16-specific IgG among patients with HPVOPC, their long-term sexual partners, and healthy volunteers. Risk factor surveys and rinse and gargle specimens were collected. Peripheral blood samples at diagnosis were evaluated for IgG Abs to HPV16 antigens using a programmable ELISA assay. Predictors for HPV16 serologic responses were evaluated using univariate and multivariable linear regression. RESULTS 116 patients with HPVOPC, 43 partners, and 81 healthy volunteers were enrolled and had baseline sera for analysis. Cases were primarily male (90%), with a median age of 56 years. Abs to E1, E2, E6 or E7 antigens were detected more often in HPVOPC compared with volunteers or partner sera (p<0.0001). HPV16 Abs to at least one early protein (E1, E2, E4, E5, E6, or E7) were detected in the sera of 90.6% of cases, 0% of partners and 7.4% of healthy volunteers. Gender, race, sexual behavior, and viral integration were not associated with antibody response. Younger age and higher oral HPV16 copy number were associated with higher HPV16 E6 and NE2 antibody levels. CONCLUSIONS HPV16 seroreactivity is commonly detected among patients with HPVOPC at diagnosis, but not among partners or healthy volunteers. Seroreactivity among cases are correlated with viral load and stage and not with other demographic or behavioral factors. Positive HPV16 serology was strongly associated with HPV 16 oropharyngeal cancer.
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28
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Anderson KS, Dahlstrom KR, Cheng JN, Alam R, Li G, Wei Q, Gross ND, Chowell D, Posner M, Sturgis EM. HPV16 antibodies as risk factors for oropharyngeal cancer and their association with tumor HPV and smoking status. Oral Oncol 2015; 51:662-7. [PMID: 25957822 DOI: 10.1016/j.oraloncology.2015.04.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2015] [Revised: 03/16/2015] [Accepted: 04/15/2015] [Indexed: 01/27/2023]
Abstract
BACKGROUND Antibodies (Abs) to the HPV16 proteome increase risk for HPV-associated OPC (HPVOPC). The goal of this study was to investigate the association of a panel of HPV16 Abs with risk for OPC as well as the association of these Abs with tumor HPV and smoking status among patients with OPC. METHODS IgG Abs to the HPV16 antigens E1, E2, E4, E5, E6, E7, L1, L2 were quantified using a programmable ELISA assay. Sera were obtained from 258 OPC patients at diagnosis and 250 healthy controls. HPV16 tumor status was measured by PCR for 137 cases. Multivariable logistic regression was used to calculate odds ratios for the association of HPV16 Abs with risk for OPC. RESULTS HPV16 E1, E2, E4, E5, E6, E7 and L1-specific IgG levels were elevated in OPC patients compared to healthy controls (p<0.05). After multivariable adjustment, Ab positivity for NE2, CE2, E6, and/or E7 was associated with OPC risk (OR [95% CI], 249.1 [99.3-624.9]). Among patients with OPC, Ab positivity for these antigens was associated with tumor HPV status, especially among never or light smokers (OR [95% CI], 6.5 [2.1-20.1] and OR [95% CI], 17.5 [4.0-77.2], respectively). CONCLUSIONS Antibodies to HPV16 proteins are associated with increased risk for HPVOPC. Among patients with OPC, HPV16 Abs are associated with tumor HPV status, in particular among HPV positive patients with no or little smoking history.
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Affiliation(s)
- Karen S Anderson
- Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, AZ, United States.
| | - Kristina R Dahlstrom
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Julia N Cheng
- Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Rizwan Alam
- Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Guojun Li
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, United States
| | - Neil D Gross
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Diego Chowell
- Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, AZ, United States; Simon A. Levin Mathematical, Computational, and Modeling Sciences Center, Arizona State University, Tempe, AZ, United States
| | - Marshall Posner
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, United States
| | - Erich M Sturgis
- Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Gunasekera SK, Perera KA, Fernando C, Udagama PV. A shifting paradigm in the aetiology of oral and pharyngeal cancer in Sri Lanka: a case-control study providing serologic evidence for the role of oncogenic HPV types 16 and 18. Infect Agent Cancer 2015; 10:12. [PMID: 25908938 PMCID: PMC4407420 DOI: 10.1186/s13027-015-0007-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 03/31/2015] [Indexed: 02/08/2023] Open
Abstract
Background Oral and pharyngeal cancer (OPC) of multifactorial aetiology is a major health problem globally. Ranking first in all cancers, OPC poses a significant impact on the Sri Lankan male population. As Human Papillomavirus (HPV) high risk (HR) types are found to be significant risk factors for OPC globally, the current study was undertaken to examine the association between HR-HPV16 and 18 types with OPC in Sri Lanka. Materials and methods Serum samples of 78 OPC patients and 51 non-cancer controls were assayed for the presence of anti-HPV16 and anti-HPV18 IgG antibodies using in-house established Enzyme Linked Immunosorbent Assays (ELISAs). The association between OPC and its risk factors i.e. HPV, smoking, alcohol, betel quid, poor dentition, was established using Chi-square test. Logistic regression was used to calculate odds ratios (OR), adjusted for the influence of other risk factors. Results This prototype study in Sri Lanka showed a significant risk of 15 fold in developing OPC due to HPV16/18 seropositivity after removing variability due to other factors. Oncogenic HPV18 showed a higher rate of seropositivity being detected in 32% of OPC patients, and also in 2% of non-cancer control subjects. HR-HPV16 was detected in 23% of OPC patients and in 5.88% of controls. Moreover, seven OPC patients were detected with both anti-HPV16 and anti-HPV18 antibodies. According to the logistic regression models HPV18 seropositivity was associated with a 28 fold risk in developing OPC while that of HPV16 was associated with a 6 fold increase in risk for the development of OPC. A 5 fold risk of developing OPC was also pronounced among smokers while alcohol, betel and poor dentition was not significantly associated with OPC. Statistically significant differences with regard to age, gender, smoking, alcohol, betel use, poor dentition and site specificity of the tumour was not observed between HPV seropositive and seronegative OPC patients. Conclusions Both in-house developed ELISAs detected significant proportions of HPV seropositives within the OPC study population suggestive of HPV as a strong risk factor for oral and pharyngeal carcinogenesis in Sri Lanka.
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Affiliation(s)
| | | | | | - Preethi Vidya Udagama
- Department of Zoology, Faculty of Science, University of Colombo, Colombo 03, Sri Lanka
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30
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Lang Kuhs KA, Anantharaman D, Waterboer T, Johansson M, Brennan P, Michel A, Willhauck-Fleckenstein M, Purdue MP, Holcátová I, Ahrens W, Lagiou P, Polesel J, Simonato L, Merletti F, Healy CM, Kjaerheim K, Conway DI, Macfarlane TV, Thomson P, Castellsagué X, Znaor A, Black A, Huang WY, Krogh V, Trichopoulou A, Bueno-de-Mesquita HBA, Clavel-Chapelon F, Weiderpass E, Ekström J, Riboli E, Tjønneland A, Sánchez MJ, Travis RC, Hildesheim A, Pawlita M, Kreimer AR. Human Papillomavirus 16 E6 Antibodies in Individuals without Diagnosed Cancer: A Pooled Analysis. Cancer Epidemiol Biomarkers Prev 2015; 24:683-9. [PMID: 25623733 PMCID: PMC4383678 DOI: 10.1158/1055-9965.epi-14-1217] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 12/16/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND The increasing incidence of oropharyngeal cancer in many developed countries has been attributed to human papillomavirus type 16 (HPV16) infections. Recently, HPV16 E6 serology has been identified as a promising early marker for oropharyngeal cancer. Therefore, characterization of HPV16 E6 seropositivity among individuals without cancer is warranted. METHODS A total of 4,666 controls were pooled from several studies of cancer and HPV seropositivity, all tested within the same laboratory. HPV16 E6 seropositive controls were classified as having (i) moderate [mean fluorescent intensity (MFI) ≥ 484 and <1,000] or (ii) high seroreactivity (MFI ≥ 1,000). Associations of moderate and high HPV16 E6 seroreactivity with (i) demographic risk factors; and seropositivity for (ii) other HPV16 proteins (E1, E2, E4, E7, and L1), and (iii) E6 proteins from non-HPV16 types (HPV6, 11, 18, 31, 33, 45, and 52) were evaluated. RESULTS Thirty-two (0.7%) HPV16 E6 seropositive controls were identified; 17 (0.4%) with moderate and 15 (0.3%) with high seroreactivity. High HPV16 E6 seroreactivity was associated with former smoking [odds ratio (OR), 5.5; 95% confidence interval (CI), 1.2-51.8], and seropositivity against HPV16 L1 (OR, 4.8; 95% CI, 1.3-15.4); E2 (OR, 7.7; 95% CI, 1.4-29.1); multiple HPV16 proteins (OR, 25.3; 95% CI, 2.6-119.6 for three HPV16 proteins beside E6) and HPV33 E6 (OR, 17.7; 95% CI, 1.9-81.8). No associations were observed with moderate HPV16 E6 seroreactivity. CONCLUSIONS High HPV16 E6 seroreactivity is rare among individuals without diagnosed cancer and was not explained by demographic factors. IMPACT Some HPV16 E6 seropositive individuals without diagnosed HPV-driven cancer, especially those with seropositivity against other HPV16 proteins, may harbor a biologically relevant HPV16 infection.
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Affiliation(s)
| | | | - Tim Waterboer
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Paul Brennan
- International Agency for Research on Cancer (IARC), Lyon, France
| | | | | | - Mark P Purdue
- National Cancer Institute, NIH, Bethesda, Maryland. Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Ivana Holcátová
- Charles University in Prague, 1st Faculty of Medicine, Prague, Czech Republic
| | - Wolfgang Ahrens
- Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany
| | | | | | - Lorenzo Simonato
- Laboratory of Public Health and Population Studies, Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Franco Merletti
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Claire M Healy
- Trinity College School of Dental Science, Dublin, Ireland
| | | | - David I Conway
- University of Glasgow, Glasgow, United Kingdom. University of Aberdeen, Aberdeen, United Kingdom
| | | | - Peter Thomson
- University of Newcastle on Tyne, Newcastle, United Kingdom
| | - Xavier Castellsagué
- Unit of Infections and Cancer, Institut Català d'Oncologia (ICO), IDIBELL, CIBERESP, L'Hospitalet de Llobregat, Catalonia, Spain
| | - Ariana Znaor
- Croatian National Institute of Public Health, Zagreb, Croatia
| | - Amanda Black
- National Cancer Institute, NIH, Bethesda, Maryland
| | - Wen-Yi Huang
- National Cancer Institute, NIH, Bethesda, Maryland
| | - Vittorio Krogh
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Antonia Trichopoulou
- Hellenic Health Foundation, Athens, Greece. Academy of Athens, Athens, Greece. University of Athens Medical School, Athens, Greece
| | - H B As Bueno-de-Mesquita
- National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. University Medical Centre, Utrecht, the Netherlands. The School of Public Health, Imperial College London, London, United Kingdom. University of Malaya, Kuala Lumpur, Malaysia
| | - Françoise Clavel-Chapelon
- Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France. Université Paris Sud, Villejuif, France. Institut Gustave Roussy, Villejuif, France
| | - Elisabete Weiderpass
- Department of Research, Cancer Registry of Norway, Oslo, Norway. Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland
| | - Johanna Ekström
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Elio Riboli
- Imperial College London, London, United Kingdom
| | | | - María-José Sánchez
- Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
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Combes JD, Pawlita M, Waterboer T, Hammouda D, Rajkumar T, Vanhems P, Snijders P, Herrero R, Franceschi S, Clifford G. Antibodies against high-risk human papillomavirus proteins as markers for invasive cervical cancer. Int J Cancer 2014; 135:2453-61. [PMID: 24729277 DOI: 10.1002/ijc.28888] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 03/13/2014] [Accepted: 03/21/2014] [Indexed: 12/26/2022]
Abstract
Different human papillomavirus (HPV) genes are expressed during the various phases of the HPV life cycle and may elicit immune responses in the process towards malignancy. To evaluate their association with cervical cancer, antibodies against proteins from HPV16 (L1, E1, E2, E4, E6 and E7) and HPV18/31/33/35/45/52/58 (L1, E6 and E7) were measured in serum of 307 invasive cervical cancer cases and 327 controls from Algeria and India. Antibody response was evaluated using a glutathione S-transferase-based multiplex serology assay and HPV DNA detected from exfoliated cervical cells using a GP5+/6+-mediated PCR assay. Among HPV16 DNA-positive cases, seroprevalence of HPV16 antibodies ranged from 16% for HPV16 E1 to 50% for HPV16 E6 and all were significantly higher than controls. Seroprevalence of E6, E7 and L1 antibodies for HPV18 and for at least one of HPV31/33/35/45/52/58 were also higher in cases positive for DNA of the corresponding type (50% and 30% for E6 of HPV18 and HPV31/33/35/45/52/58 combined, respectively). E6 and E7 antibodies were rarely found in controls, but cross-reactivity was evident among cancer cases positive for DNA of closely phylogenetically-related HPV types. E6 or E7 antibodies against any of the eight HPV types were detected in 66.1% of all cervical cancer cases, as compared to 10.1% of controls. E6, and to a lesser extent E7, antibodies appear to be specific markers of HPV-related malignancy. However, even among cases positive for the same type of HPV DNA, approximately one-third of cervical cancer cases show no detectable immune response to either E6 or E7.
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What are the implications of human papillomavirus status in oropharyngeal tumors for clinical practice? Curr Opin Otolaryngol Head Neck Surg 2014; 22:90-4. [PMID: 24492854 DOI: 10.1097/moo.0000000000000030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE OF REVIEW Human papillomavirus (HPV) status itself is an important and very probably the strongest prognostic factor in head and neck cancer. Because of the prognostic advantage of patients with HPV-positive cancers, the issue of the quality of life of survivors has become increasingly important. The possibility of treatment de-escalation in patients with virally induced tumors is being considered. Many challenges have to be addressed in order to integrate HPV status in the routine decision-making in patients with oropharyngeal cancer. The present review discusses the standardization of detection methods suitable for clinical use and the differences in predictive parameters between patients with HPV-positive and HPV-negative tumors. RECENT FINDINGS The gold standard for the identification of patients with oropharyngeal tumors etiologically linked to HPV infection is undoubtedly the detection of HPV 16 E6/E7 mRNA. The detection of a surrogate marker of active viral infection, p16ink4a, has a low sensitivity when used alone and must therefore be combined with the detection of HPV DNA or HPV-specific antibodies. The detailed knowledge of the importance of specific prognostic parameters is crucial in the choice of treatment. Nodal staging is probably much less important in HPV-positive cancers. SUMMARY It is of great importance to implement standardized testing for the identification of patients with HPV-induced oropharyngeal tumors. The treatment decision models in HPV-positive tumors have to take into account the probably different prognostic value of nodal parameters. Before introducing treatment de-escalation in patients with virally induced tumors into clinical practice, more research and clinical studies are needed.
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Levovitz C, Chen D, Ivansson E, Gyllensten U, Finnigan JP, Alshawish S, Zhang W, Schadt EE, Posner MR, Genden EM, Boffetta P, Sikora AG. TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer. Cancer Res 2014; 74:6833-44. [PMID: 25273091 DOI: 10.1158/0008-5472.can-14-0602-t] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein-protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38-MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV(+) head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer.
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Affiliation(s)
- Chaya Levovitz
- The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Dan Chen
- SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Emma Ivansson
- SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Ulf Gyllensten
- SciLifeLab Uppsala, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - John P Finnigan
- The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Sara Alshawish
- The Icahn School of Medicine at Mount Sinai, New York, New York
| | - Weijia Zhang
- Mount Sinai Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eric E Schadt
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Mount Sinai Institute for Genomics and Multiscale Biology, New York, New York
| | - Marshal R Posner
- The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eric M Genden
- The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Genetics and Pathology, Tisch Cancer Institute, New York, New York
| | - Paolo Boffetta
- The Icahn School of Medicine at Mount Sinai, New York, New York. Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Genetics and Pathology, Tisch Cancer Institute, New York, New York
| | - Andrew G Sikora
- The Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Icahn School of Medicine at Mount Sinai, New York, New York. Department of Immunology, Genetics and Pathology, Tisch Cancer Institute, New York, New York.
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Woods RSR, O’Regan EM, Kennedy S, Martin C, O’Leary JJ, Timon C. Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review. World J Clin Cases 2014; 2:172-193. [PMID: 24945004 PMCID: PMC4061306 DOI: 10.12998/wjcc.v2.i6.172] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 04/21/2014] [Accepted: 05/19/2014] [Indexed: 02/05/2023] Open
Abstract
Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.
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35
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Pytynia KB, Dahlstrom KR, Sturgis EM. Epidemiology of HPV-associated oropharyngeal cancer. Oral Oncol 2014; 50:380-6. [PMID: 24461628 PMCID: PMC4444216 DOI: 10.1016/j.oraloncology.2013.12.019] [Citation(s) in RCA: 355] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 11/12/2013] [Accepted: 12/17/2013] [Indexed: 02/06/2023]
Abstract
Squamous cell carcinoma of the oropharynx is increasing in incidence in epidemic proportion. This site specific increase in incidence is due to an increase in human papillomavirus (HPV)-related squamous cell carcinoma, while the incidence of tobacco related squamous cell carcinoma is decreasing. In particular, the incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is increased among middle aged white men, and sexual behavior is a risk factor. HPV-related oropharyngeal squamous cell carcinoma represents a growing etiologically distinct subset of head and neck cancers with unique epidemiological, clinical, and molecular characteristics that differ from those of HPV-unassociated cancers. In this review, we discuss the epidemiology of HPV-related OPSCC, the prevalence of oral/oropharyngeal HPV infection, and efforts aimed at reducing the incidence of HPV-related OPSCC.
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Affiliation(s)
- Kristen B Pytynia
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
| | - Kristina R Dahlstrom
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Erich M Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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36
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Michaud DS, Langevin SM, Eliot M, Nelson HH, Pawlita M, McClean MD, Kelsey KT. High-risk HPV types and head and neck cancer. Int J Cancer 2014; 135:1653-61. [PMID: 24615247 DOI: 10.1002/ijc.28811] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 02/07/2014] [Accepted: 02/11/2014] [Indexed: 12/25/2022]
Abstract
Although HPV16 has been strongly implicated in oropharyngeal carcinogenesis, the role of other high-risk HPV types in the etiology of head and neck cancer remains unclear. To date, few data exist addressing the nature of the association between antibodies to oncogenic proteins of non-HPV16 HPVs in relation to head and neck cancer. We examined the relationship between multiple HPV types (HPV6, 11, 16, 18, 31, 33, 45, 52, 58) and head and neck squamous cell carcinoma (HNSCC) in a large population-based case-control study (1069 cases and 1107 controls). Serological measures for HPV types included antibodies to L1, E6 and/or E7. In a secondary analysis, we excluded HPV16 seropositive subjects to examine independent associations with other high-risk HPVs. All analyses were adjusted for age, race, sex, education, smoking and alcohol consumption. Statistically significant associations were observed for HPV16, 18, 33 and 52 and risk of HNSCC after mutually adjusting for HPV types. Among HPV16 seronegative subjects, elevated risks of HNSCC were observed for HPV18 E6 (OR = 4.19, 95% CI = 1.26-14.0), HPV33 E6 (OR = 7.96, 95% CI = 1.56-40.5) and HPV52 E7 (OR = 3.40, 95% CI = 1.16-9.99). When examined by tumor type, associations with HPV18 and HPV33 remained statistically significant for oropharyngeal cancer, and HPV52 was associated with oral cancer. In addition, magnitude of associations for HNSCC increased markedly with increasing number of seropositive high-risk HPV infections. High-risk HPV types, other than HPV16, are likely to be involved in the etiology of HNSCC.
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Affiliation(s)
- Dominique S Michaud
- Department of Epidemiology, Brown School of Public Health, Brown University, Providence, RI; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
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37
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López RVM, Levi JE, Eluf-Neto J, Koifman RJ, Koifman S, Curado MP, Michaluart-Junior P, Figueiredo DLA, Saggioro FP, de Carvalho MB, Kowalski LP, Abrahão M, de Góis-Filho F, Tajara EH, Waterboer T, Boffetta P, Brennan P, Wünsch-Filho V. Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection. Cancer Causes Control 2014; 25:461-71. [PMID: 24474236 DOI: 10.1007/s10552-014-0348-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 01/15/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND The role of human papillomavirus (HPV) on head and neck squamous cell carcinoma (HNSCC) survival in regions with low HPV prevalence is not yet clear. We evaluated the HPV16 infection on survival of HNSCC Brazilian patient series. METHODS This cohort comprised 1,093 HNSCC cases recruited from 1998 to 2008 in four Brazilian cities and followed up until June 2009. HPV16 antibodies were analyzed by multiplex Luminex assay. In a subset of 398 fresh frozen or paraffin blocks of HNSCC specimens, we analyzed for HPV16 DNA by L1 generic primer polymerase chain reaction. HNSCC survival according to HPV16 antibodies was evaluated through Kaplan-Meier method and Cox regression. RESULTS Prevalence of HPV16 E6 and E6/E7 antibodies was higher in oropharyngeal cancer than in other head and neck tumor sites. HPV16 DNA positive in tumor tissue was also higher in the oropharynx. Seropositivity for HPV16 E6 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer. The presence of HPV16 E6/E7 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer survival. The death risk of oropharyngeal squamous cell carcinoma patients HPV16 E6/E7 antibodies positive was 78 % lower than to those who test negative. CONCLUSION Oropharyngeal squamous cell carcinoma is less aggressive in the HPV16 E6/E7 positive serology patients. HPV16 E6/E7 antibody is a clinically sensible surrogate prognostic marker of oropharyngeal squamous cell carcinoma.
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38
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Wong GR, Ha KO, Himratul-Aznita WH, Yang YH, Wan Mustafa WM, Yuen KM, Abraham MT, Tay KK, Karen-Ng LP, Cheong SC, Zain RB. Seropositivity of HPV 16 E6 and E7 and the risk of oral cancer. Oral Dis 2014; 20:762-7. [PMID: 24320099 DOI: 10.1111/odi.12218] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 11/03/2013] [Accepted: 11/18/2013] [Indexed: 12/29/2022]
Abstract
OBJECTIVES The objective of the study was to determine the prevalence of HPV seropositivity among patients with oral squamous cell carcinoma (OSCC) and healthy individuals and to correlate the association between HPV 16 seropositivity and risk of OSCC. MATERIALS AND METHODS HPV 16 E6 and E7 plasmids were constructed for the production of recombinant protein, which was used as the antigen in ELISA. HPV ELISA was performed on serum samples from 50 healthy individuals and 50 patients with OSCC. RESULTS Using the HPV ELISA, 30% (OR = 2.25, 95% CI = 0.85-5.93) and 18% (OR = 1.61, 95% CI = 0.53-4.92) of patients with oral cancer were found to be HPV 16 E6 and E7 seropositive, respectively. Significant association was found between HPV 16 seropositivity and increased risk of OSCC in men, but not in male subjects. A similar trend was observed in non-betel quid chewers. CONCLUSIONS Potential associations between HPV 16 E6/E7 seropositivity and oral cancer were revealed in men and non-betel quid chewer subjects, suggesting a possible etiological role of HPV 16 in subgroup of patients with OSCC in Malaysia.
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Affiliation(s)
- G R Wong
- Oral Cancer Research & Coordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia; Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
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He Z, Xu Z, Hang D, Guo F, Abliz A, Weiss NS, Xi L, Liu F, Ning T, Pan Y, Guo C, Liang Y, Lu C, Zhang L, Cai H, Ke Y. Anti-HPV-E7 seropositivity and risk of esophageal squamous cell carcinoma in a high-risk population in China. Carcinogenesis 2013; 35:816-21. [PMID: 24356570 DOI: 10.1093/carcin/bgt483] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Results of previous serologic studies on the association of human papillomavirus (HPV) with esophageal squamous cell carcinoma (ESCC) have been inconsistent. From 2007 to 2010, the authors collected blood samples and relevant demographic data from 1435 patients with ESCC and 2071 age- and sex-matched normal controls from Anyang, China. HPV-16, 18 and 57 E7 antibodies were evaluated with the glutathione-S-transferase capture ELISA. The proportions of subjects who were positive for antibodies against these three HPV antigens in the case group were all significantly higher than those in the control group. In multivariate analysis, the presence of HPV-16 E7 antibody was associated with an increased risk of ESCC [odds ratio (OR) = 3.6, 95% confidence interval (CI): 2.5-5.0], whereas the presence of HPV-18 (OR = 1.1, 95% CI: 0.7-1.7) and HPV-57 (OR = 1.3, 95% CI: 0.9-1.9) antibodies were not significant after adjustment for HPV-16. In multiple cutoff value analysis, the lowest OR for HPV-16 was obtained with the standard cut point mean + 3 SD. This study provides serological evidence in support of HPV-16 infection playing a role in the occurrence of ESCC in a high-incidence area of China.
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Affiliation(s)
- Zhonghu He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Beijing 100142, P.R. China
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Hashibe M, Sturgis EM. Epidemiology of oral-cavity and oropharyngeal carcinomas: controlling a tobacco epidemic while a human papillomavirus epidemic emerges. Otolaryngol Clin North Am 2013; 46:507-20. [PMID: 23910467 DOI: 10.1016/j.otc.2013.05.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Although tobacco prevalence is declining in most developed countries, less developed countries are still experiencing an increase in tobacco use. Thus the future burden of oral-cavity and oropharyngeal cancers in less developed countries is expected to be heavy. The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer is dramatically increasing in the United States and other developed countries, although trends in less developed countries are not clear at present. HPV vaccine compliance in the United States is low, although it continues to increase each year. Increasing the HPV vaccination rate to control future HPV-associated cancer incidence remains a priority.
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Affiliation(s)
- Mia Hashibe
- Division of Public Health, Department of Family & Preventive Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, 375 Chipeta Way, Suite A, Salt Lake City, UT 84108, USA.
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41
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Gillison ML, Alemany L, Snijders PJF, Chaturvedi A, Steinberg BM, Schwartz S, Castellsagué X. Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine 2013. [PMID: 23199965 DOI: 10.1016/j.vaccine.2012.05.070] [Citation(s) in RCA: 198] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Human papillomavirus (HPV) infection is causally associated with benign and malignant diseases of the upper airway, including respiratory papillomatosis and oropharyngeal cancer. Low-risk HPV types 6 and 11 are the predominant cause of papillomatosis, whereas only HPV16 definitively satisfies both molecular and epidemiological causal criteria as a carcinogenic or high-risk type in the upper airway. HPV16 E6/E7 mRNA expression and integration are observed predominantly among oropharyngeal cancers, and experimental models have shown E6/E7 expression to be necessary for the initiation and maintenance of the malignant phenotype of these cancers. From an epidemiological perspective, a strong and consistent association between markers of HPV16 exposure and oropharyngeal cancer has been demonstrated in numerous case-control studies. HPV-positive oropharyngeal cancers have also been shown to be distinct from HPV-negative head and neck squamous cell cancers with regard to risk-factor profiles, molecular genetic alterations, population-level incidence trends over time, and prognosis. Tumor HPV status (as determined by certain HPV16 in situ hybridization assays or certain p16 immunohistochemistry assays) is the strongest determinant of survival for patients with local-regionally advanced oropharyngeal cancer: patients with HPV-positive cancer have at least a 50% improvement in overall survival at 5 years, which is equivalent to an approximate 30% difference in absolute survival. Thus, HPV status determination is now part of the routine diagnostic evaluation for prognostication. Preliminary evidence indicates that a small proportion of head and neck cancers may be caused by additional HPV types (e.g., 18, 31, 33, 35) and that HPV-caused cancers may rarely arise from non-oropharyngeal sites (e.g., the oral cavity, nasopharynx, and larynx). Whether or not HPV vaccination has the potential to prevent oral HPV infections that lead to cancer or papillomatosis in the upper airway is currently unknown, as is the potential for secondary prevention with HPV detection. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.
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Affiliation(s)
- Maura L Gillison
- Viral Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
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42
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Koslabova E, Hamsikova E, Salakova M, Klozar J, Foltynova E, Salkova E, Rotnaglova E, Ludvikova V, Tachezy R. Markers of HPV infection and survival in patients with head and neck tumors. Int J Cancer 2013; 133:1832-9. [DOI: 10.1002/ijc.28194] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 03/21/2013] [Indexed: 11/06/2022]
Affiliation(s)
| | - Eva Hamsikova
- Department of Experimental Virology; Institute of Hematology and Blood Transfusion; Prague; Czech Republic
| | - Martina Salakova
- Department of Experimental Virology; Institute of Hematology and Blood Transfusion; Prague; Czech Republic
| | - Jan Klozar
- Department of Otorhinolaryngology and Head and Neck Surgery, First Faculty of Medicine; Charles University in Prague; Motol University Hospital; Prague; Czech Republic
| | | | - Eva Salkova
- Department of Pathology and Molecular Medicine, Second Faculty of Medicine; Charles University in Prague; Prague; Czech Republic
| | | | - Viera Ludvikova
- Department of Experimental Virology; Institute of Hematology and Blood Transfusion; Prague; Czech Republic
| | - Ruth Tachezy
- Department of Experimental Virology; Institute of Hematology and Blood Transfusion; Prague; Czech Republic
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Abstract
An increasing subset of patients with head and neck squamous cell carcinoma (HNSCCA) is positive for high-risk human papillomavirus (HR-HPV). Patients tend to be younger, have a minimal or absent tobacco and ethanol abuse history, increased number of lifetime sexual partners (particularly oral-genital sex), and squamous cell carcinomas (SCCAs) arising in the oropharynx. The most common HR-HPV associated with HNSCCA is HPV-16. HR-HPV positivity is associated with decreased expression of the p53 and Rb genes, overexpression of p16, decreased expression of EGFR, and a different genetic expression pattern compared with patients with HR-HPV-negative SCCAs, leading to the conclusion that this is a distinct clinical entity. Patients who have HR-HPV-positive HNSCCAs have an improved prognosis, particularly those with oropharyngeal SCCAs, leading some to speculate that the intensity of treatment might be decreased. At present, whether this can be done safely remains unclear.
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Anantharaman D, Gheit T, Waterboer T, Abedi-Ardekani B, Carreira C, McKay-Chopin S, Gaborieau V, Marron M, Lagiou P, Ahrens W, Holcátová I, Merletti F, Kjaerheim K, Talamini R, Simonato L, Castellsague X, Macfarlane TV, Biggs AM, Thakker N, Znaor A, Thomson P, Canova C, Conway DI, Healy CM, Tommasino M, Pawlita M, Brennan P. Human papillomavirus infections and upper aero-digestive tract cancers: the ARCAGE study. J Natl Cancer Inst 2013; 105:536-45. [PMID: 23503618 DOI: 10.1093/jnci/djt053] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Human papillomavirus (HPV) is causally implicated in a subset of cancers of the upper aero-digestive tract (UADT). METHODS Associations between type-specific HPV antibodies were examined among 1496 UADT cancer case subjects and 1425 control subjects by estimating odds ratios (ORs) in logistic regression analyses adjusted for potential confounders. The agreement between serology and tumor markers of HPV infection, including presence of HPV DNA and p16 expression, were examined in a subset of tumors. RESULTS HPV16 L1 seropositivity was associated with increased risk of oral cavity and oropharyngeal cancer (OR = 1.94, 95% confidence interval [CI] = 1.03 to 3.65; OR = 8.60, 95% CI = 5.21 to 14.20, respectively). HPV16 E6 antibodies were present in 30.2% of oropharyngeal case subjects and only 0.8% of control subjects (OR = 132.0, 95% CI = 65.29 to 266.86). Combined seropositivity to HPV16 E6 and E7 was rare (n = 1 of 1425 control subjects). An agreement of 67% was observed between HPV16 E6 serology and the corresponding presence of an HPV-related cancer: four of six HPV DNA-positive/p16-overexpressing tumors were HPV16 E6 antibody positive. An HPV16 independent association was observed for HPV18 and oropharyngeal cancer (OR = 8.14, 95% CI = 2.21 to 29.99 for HPV18 E6 seropositivity) and HPV6 and laryngeal cancer (OR = 3.25, 95% CI = 1.46 to 7.24 for HPV6 E7 seropositivity). CONCLUSIONS These results confirm an important role for HPV16 infection in oropharyngeal cancer. HPV16 E6 antibodies are strongly associated with HPV16-related oropharyngeal cancers. Continuing efforts are needed to consider both HPV serology and p16 staining as biomarkers relevant to the etiology and natural history of HPV16-related oropharyngeal tumors. These results also support a marginal role for HPV18 in oropharyngeal cancer and HPV6 in laryngeal cancer.
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Affiliation(s)
- Devasena Anantharaman
- Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France
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Abstract
Recent data show that human papillomavirus-positive oropharyngeal cancer (OPC) has a distinct biological and clinical behavior compared with human papillomavirus-negative OPC. As this subset of head and neck cancer represents an increasing public health concern, a thorough understanding of the causative and mechanistic differences between these diseases and how these distinctions impact clinical treatment is required. In this review, we will summarize recent data in epidemiology, the mechanism of viral carcinogenesis and differences in tumor biology that may provide insights to improve the clinical management of patients with human papillomavirus-positive OPC.
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Affiliation(s)
- Jason D Howard
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA
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47
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Liang C, Marsit CJ, McClean MD, Nelson HH, Christensen BC, Haddad RI, Clark JR, Wein RO, Grillone GA, Houseman EA, Halec G, Waterboer T, Pawlita M, Krane JF, Kelsey KT. Biomarkers of HPV in head and neck squamous cell carcinoma. Cancer Res 2012; 72:5004-13. [PMID: 22991304 DOI: 10.1158/0008-5472.can-11-3277] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Human papillomavirus (HPV) is an accepted cause of head and neck squamous cell carcinoma (HNSCC), and patients with HPV-associated HNSCC have a favorable prognosis. Currently, there is no general guidance on the most appropriate biomarkers for clinical assessment of HPV in these malignancies. We compared PCR-based and serologic HPV assays, as well as p16 immunohistochemistry, individually and in combination in a single population-based study to assess their associations with overall survival among patients with HNSCC, and thus their potential value as biomarkers. HPV16 serology was determined for 488 patients; immunohistochemical detection of p16 expression in tumors was conducted in a subset of 233 cases, and PCR-based methods to assess the presence of HPV16 DNA in a subset of 179 cases of tumors. Considering each biomarker individually in the subset of patients studied for all endpoints, seropositivity for the E6 and E7 proteins was significantly associated with enhanced all-cause survival in oropharyngeal disease [HR(E6/E7+) = 0.1, 95% confidence interval (CI) = 0.02-0.3]. Neither the presence of HPV16 DNA nor p16 immunostaining was associated with significant enhanced overall survival in oropharyngeal disease (HR(DNA) = 0.9, 95% CI = 0.3-2.9; HR(p16) = 0.3, 95% CI = 0.1-1.1). However, the combination of HPV-positive DNA and E6 or E7 serology was associated with enhanced overall survival in oropharyngeal disease (HR(DNA+/E6/E7+) = 0.1, 95% CI = 0.02-1.0), whereas E6/E7 seronegative patients with evidence of HPV in tumor DNA did not show any evidence of favorable survival (HR(DNA+/E6-/E7-) = 3.4, 95% CI = 0.6-18.1). Furthermore, patients with p16 staining and E6 or E7 seropositivity had favorable survival from oropharyngeal disease (HR(p16+/E6/E7+) = 0.1, 95% CI = 0.02-0.4), whereas patients who were p16 positive and E6/E7 seronegative had significantly increased hazard of all causes of death (HR(p16+/E6-/E7-) = 3.1, 95% CI = 1.2-7.7). A stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when "HPV-associated" HNSCC is defined using tumor status (HPV DNA status or P16) and HPV E6/E7 serology in combination rather using tumor HPV status alone.
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Affiliation(s)
- Caihua Liang
- Department of Epidemiology, Division of Biology and Medicine, Brown University, Providence, Rhode Island, USA
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48
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Chaturvedi AK. Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol 2012; 6 Suppl 1:S16-24. [PMID: 22782220 PMCID: PMC3394159 DOI: 10.1007/s12105-012-0377-0] [Citation(s) in RCA: 157] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 06/07/2012] [Indexed: 12/18/2022]
Abstract
Human papillomavirus (HPV) infection is now established as a major etiologic factor for oropharyngeal cancers. Case-control studies conducted around the world show strong and consistent associations of markers of HPV exposure with risk of oropharyngeal cancers (range of odds ratios [OR] for oral oncogenic HPV infections = 3.6-230.0, ORs for HPV16 L1 antibodies = 2.3-182.0, and ORs for HPV16 E6/E7 antibodies = 9.2-231.0. HPV-positive oropharyngeal cancers are epidemiologically distinct from HPV-negative ones, and are characterized by younger age at onset, male predominance, and strong association with sexual behaviors. Importantly, HPV-positive oropharyngeal cancer patients have substantially improved outcomes (28-80 % reductions in the risk of death) than HPV-negative patients. Given the superior survival, younger age, and good performance status of HPV-positive oropharyngeal cancer patients, de-intensified therapies are currently being considered for this group of patients. Recent analyses of cancer registry data show dramatic increases in incidence of oropharyngeal cancers during the past 15-20 years in several parts of the world, highlighting the need for prevention strategies. If proven efficacious, currently available prophylactic HPV vaccines hold great promise for primary prevention of HPV-associated oropharyngeal cancers.
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Affiliation(s)
- Anil K. Chaturvedi
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, EPS 7072, Rockville, MD 20852 USA
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Hamsikova E, Ludvikova V, Stasikova J, Tachezy R. Cross-sectional study on the prevalence of HPV antibodies in the general population of the Czech Republic. Sex Transm Infect 2012; 89:133-7. [PMID: 22683892 PMCID: PMC3595147 DOI: 10.1136/sextrans-2012-050486] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Objectives The assessment of the prevalence of antibodies to human papillomaviruses (HPV) in the healthy population is essential for effective planning of HPV vaccine implementation into the preventive programmes for HPV-associated diseases and for the prospective monitoring of the impact of HPV vaccines in the Czech population. Methods The seropositivity for HPV-6, 11, 16, 18, 31 and 33 virus-like particles was determined in sera from 3150 healthy individuals (age range 6–76 years) by means of enzyme-linked immunoassay. Results The seroprevalences for HPV-6, 11, 16, 18, 31 and 33 were 23.8%, 15.2%, 14.5%, 9.9%, 16.4% and 9.6% in women and 18.4%, 13.7%, 6.5%, 5.4%, 6.1% and 4.3% in men. For both genders, except for HPV11, these rates were age dependent. The prevalence of antibodies to HPV-16 and/or 18 reached the maximum of 27.0% in women 30–39 years of age and of 14.4% in men 50–59 years of age. The highest proportion of individuals' seropositive for any of the vaccine types HPV-6/11/16/18 was in 30- to 39-year-old women (50.0%) and in ≥60-year-old men (37.6%). Antibodies specific for vaccine HPV types were detected in 18.0% of children 6- to 14-year-old but in 26.4%, those older than 14 years. Conclusions The data reveal age-specific differences in the HPV seropositivity rates between healthy women and men and support the implementation of HPV vaccination in the Czech Republic before the age of 13.
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Affiliation(s)
- Eva Hamsikova
- Department of Experimental Virology, Institute of Hematology and Blood Transfusion, Praha 2, Czech Republic.
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Joseph AW, D'Souza G. Epidemiology of human papillomavirus-related head and neck cancer. Otolaryngol Clin North Am 2012; 45:739-64. [PMID: 22793850 DOI: 10.1016/j.otc.2012.04.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Human papillomavirus (HPV) is now recognized to cause a subset of head and neck squamous cell carcinomas (HNSCC). Although excessive tobacco and alcohol use continue to be important risk factors for HNSCC, epidemiologic studies suggest that more than 25% of HNSCC are now caused by HPV. The incidence of HPV-related HNSCC is increasing, highlighting the need to understand the oral HPV infections causing these cancers. This article reviews the evidence for a causal association between HPV and HNSCC, examines the changing epidemiologic trends of HNSCC, and discusses what is currently known about oral HPV infection, natural history, and transmission.
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Affiliation(s)
- Andrew W Joseph
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, JHOC 6th Floor, 601 North Caroline Street, Baltimore, MD 21287, USA
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