Oral Oncology 51 (2015) e8–e9
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Letter to the Editor Chlamydia trachomatis infection: Possible cofactor for oropharyngeal cancer development?
The preponderance of evidence shows that nearly all cervical cancers and many oropharyngeal cancers (OPCs) are due to human papillomavirus (HPV) infection [1–3]. However, only a small proportion of women infected with HPV, even high risk variants such as 16 and 18, progress to invasive cancer . Chlamydia trachomatis (CT) co-infection is believed to be a possible co-factor that tips the balance from infection to oncogenesis [5,6]. Positive associations have been observed between CT infection and squamous cell carcinoma of the cervix or its precursor lesions in most [7–14], but not all [15–17], previous epidemiologic studies that controlled for HPV infection. By analogy, we propose that CT infection may also be a cofactor for HPV-associated OPCs. CT has been extensively studied as a sexually transmitted infection (STI), most often associated with genital and anal sites of infection. In both the US and globally, CT is the most common bacterial STI with an estimated 2,860,000 and 105,700,000 cases, respectively, in 2008 [18,19]. HPV (all variants) is the most common STI with an estimated 79 million Americans currently infected, and lifetime risks of HPV acquisition for those with at least one opposite-sex partner of 84.6% for females and 91.3% for males [20,21]. There is considerable opportunity for oral infection, as while approximately three quarters of US individuals engage in oral sex, condoms are used only 6–10% of the time and oral infection prevalences range from 1.5–12% (CT) and from 2.3–7.6% (HPV) [22–29]. Given that both CT and HPV are obligate intracellular organisms, prefer similar tissues, and are both transmitted via sexual contact, it is not surprising that they may co-occur within a single individual [6,30,31]. Chlamydial infection may contribute to carcinogenesis by its possible impact upon host cell structure, gene regulation and maintenance. Infected cells experience substantial epithelial disruption, increased and unrepaired DNA double-strand breaks due to CT-induced reactive oxygen species, increased oncogenic signaling, continued proliferation, and inhibition of apoptosis [32–36]. The main tissue targets of both chlamydia and HPV are the epithelial cells lining mucosal surfaces, and such tissues are important mediators of organism immune response [37–39]. Chlamydia infection may lead to chronic persistent inﬂammation, itself associated with rapid cell division, debilitated DNA repair, oxidative stress, increased levels of prostaglandins and cytokines, inﬂammatory pathway stimulation/upregulation, and oncogenesis [40–45]. As infection-driven inﬂammation has been implicated in 15–20% of cancers, these data support the hypothesis that chlamydial infection may contribute to oncogenesis . Epidemiological data show that HPV-associated OPCs are increasing in incidence, possibly due to increasing engagement in risky sexual activities associated with oral HPV infection . http://dx.doi.org/10.1016/j.oraloncology.2014.11.015 1368-8375/Ó 2014 Elsevier Ltd. All rights reserved.
However, while the vast majority of individuals engaging in sexual activity will acquire at least one HPV infection during their lifetime, most will spontaneously clear such infections without morbidity. The need then is to identify additional factors that promote carcinogenesis. The data gathered to date point to CT as a promising candidate co-factor in OP carcinogenesis. Research explicitly examining the possible roles of oral CT infection in OP carcinogenesis should be performed. Conﬂict of interest statement None declared. Acknowledgement There was no funding associated with this work. SS was funded by the Barnes-Jewish Hospital Foundation. References  Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007;370:890–907.  Jayaprakash V, Reid M, Hatton E, Merzianu M, Rigual N, Marshall J, et al. Human papillomavirus types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: a meta-analysis, 1985–2010. Oral Oncol 2011;47:1048–54.  Zaravinos A. An updated overview of HPV-associated head and neck carcinomas. Oncotarget 2014;5:3956–69.  National Institutes of Health. National Cancer Institute. HPV and cancer. [accessed 15.10.2014].  Silva J, Cerqueira F, Medeiros R. Chlamydia trachomatis infection: implications for HPV status and cervical cancer. Arch Gynecol Obstet 2014;289:715–23.  Bhatla N, Puri K, Joseph E, Kriplani A, Iyer VK, Sreenivas V. Association of Chlamydia trachomatis infection with human papillomavirus (HPV) & cervical intraepithelial neoplasia – a pilot study. Indian J Med Res 2013;137:533–9.  Smith JS, Bosetti C, Munoz N, Herrero R, Bosch FX, Eluf-Neto J, et al. Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int J Cancer J Int Cancer 2004;111:431–9.  Koutsky LA, Holmes KK, Critchlow CW, Stevens CE, Paavonen J, Beckmann AM, et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. New England J Med 1992;327:1272–8.  Anttila T, Saikku P, Koskela P, Bloigu A, Dillner J, Ikaheimo I, et al. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA 2001;285:47–51.  Lehtinen M, Dillner J, Knekt P, Luostarinen T, Aromaa A, Kirnbauer R, et al. Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study. BMJ (Clinical research ed) 1996;312:537–9.  Wallin KL, Wiklund F, Luostarinen T, Angstrom T, Anttila T, Bergman F, et al. A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma. Int J Cancer J Int Cancer 2002;101:371–4.  Madeleine MM, Anttila T, Schwartz SM, Saikku P, Leinonen M, Carter JJ, et al. Risk of cervical cancer associated with Chlamydia trachomatis antibodies by histology, HPV type and HPV cofactors. Int J Cancer J Int Cancer 2007;120: 650–5.  Naucler P, Chen HC, Persson K, You SL, Hsieh CY, Sun CA, et al. Seroprevalence of human papillomaviruses and Chlamydia trachomatis and cervical cancer risk: nested case-control study. J Gen Virol 2007;88:814–22.
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Wiley D. Jenkins Population Health Science Program, Center for Clinical Research, Simmons Cancer Institute, Southern Illinois University School of Medicine, 801 N. Rutledge St., Springﬁeld, IL 62794-9664, United States ⇑ Tel.: +1 217 545 8717. E-mail address: [email protected]
Kelsey LeVault Population Health Science Program, Center for Clinical Research, Southern Illinois University School of Medicine, 801 N. Rutledge St., Springﬁeld, IL 62794-9664, United States Siobhan Sutcliffe Division of Public Health Sciences and The Alvin J. Siteman Cancer Center, Department of Surgery, Washington University School of Medicine, 660 S. Euclid Ave., Rm. 2-208S, Box 8100, St. Louis, MO 63110, United States Available online 12 December 2014