In the past two decades, several studies1Parkin DM The global health burden of infection-associated cancers in the year 2002.Int J Cancer. 2006; 118: 3030-3044Crossref PubMed Scopus (2233) Google Scholar, 2de Martel C Ferlay J Franceschi S et al.Global burden of cancers attributable to infections in 2008: a review and synthetic analysis.Lancet Oncol. 2012; 13: 607-615Summary Full Text Full Text PDF PubMed Scopus (1758) Google Scholar have consistently found that up to one-sixth of cancers worldwide are attributable to infectious pathogens. Cancers caused by infectious agents present unique opportunities for prevention and treatment; therefore, a detailed understanding of how infections contribute to cancer incidence, as well as the geographical and demographic diversity and natural history (ie, response to treatment and mortality) of infection-related cancers, is crucial. In The Lancet Global Health, Martyn Plummer and colleagues3Plummer M de Martel C Vignat J Ferlay J Bray F Franceschi S Global burden of cancers attributable to infections in 2012: a synthetic analysis.Lancet Glob Health. 2016; (published online July 25.)http://dx.doi.org/10.1016/S2214-109X(16)30143-7PubMed Google Scholar update an analysis of the global burden of infection-related cancers using data from GLOBOCAN 2012. As an enhancement to their previous publications, the authors now include country-level analyses of the total burden of infection-related cancers. As Plummer and colleagues acknowledge, the proportion of cancers caused by infectious agents is likely to be under-represented in this analysis. Besides the methodological reasons discussed in the Article, two additional factors might also contribute to a higher burden of infection-attributable cancers than recognised at present. First, the authors only counted cancers associated with viral infections as “HIV-associated”. A wide variety of cancers, including many that are not presently associated with pathogens (eg, lung, skin, and kidney cancers, and leukaemia), are now known to have increased prevalence in HIV-infected individuals.4Shiels MS Cole SR Kirk GD Poole C A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals.J Acquir Immune Defic Syndr. 2009; 52: 611-622Crossref PubMed Scopus (378) Google Scholar HIV is considered a group 1 carcinogen by the International Agency for Research on Cancer,5International Agency for Research and CancerAgents classified by the IARC monographs.http://monographs.iarc.fr/ENG/Classification/Google Scholar and a direct role of HIV in the genesis of many cancers is also supported by findings from several prospective cohort studies and translational research.6Kowalkowski MA Day RS Du XL Chan W Chiao EY Cumulative HIV viremia and non-AIDS-defining malignancies among a sample of HIV-infected male veterans.J Acquir Immune Defic Syndr. 2014; 67: 204-211Crossref PubMed Scopus (33) Google Scholar, 7Aoki Y Tosato G Neoplastic conditions in the context of HIV-1 infection.Curr HIV Res. 2004; 2: 343-349Crossref PubMed Scopus (38) Google Scholar Attribution of more cancers to HIV infection among the more than 36 million HIV-infected individuals worldwide would increase the proportion of infection-attributable cancers, especially in HIV-endemic regions. Second, as supported by the discovery of two new human tumour viruses in the past two decades, human herpesvirus type 8 and Merkel cell polyomavirus, there are likely to be additional cancer types that are attributable to novel infectious agents. Lung and lip cancer, as well as squamous cell carcinoma of the conjunctiva, have all been reported to have increased incidence in individuals with immunosuppression8Grulich AE van Leeuwen MT Falster MO Vajdic CM Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis.Lancet. 2007; 370: 59-67Summary Full Text Full Text PDF PubMed Scopus (1686) Google Scholar and are likely to be caused by infectious agents. Similarly, new pathogens might be identified in the cancers that are only partly attributable to infections at present, such as the substantial fraction of human-papillomavirus-negative penile, vulvar, and oropharyngeal cancers. Although the more than 2 million cases of infection-associated cancer diagnosed annually is substantial, it is notable that nearly two-thirds of such cases occur in less developed regions. It is reasonable to speculate, as the authors do, that economic disparities account for the imbalanced prevalence of infection-associated cancers worldwide. However, it is important to consider other potential contributors because they might inform the biology of infection-related cancers or point to additional prevention strategies. Immunogenetic factors affect both the acquisition of infection-causing pathogens and the rate of progression from primary infection to cancer.9Martin MP Carrington M Immunogenetics of viral infections.Curr Opin Immunol. 2005; 17: 510-516Crossref PubMed Scopus (109) Google Scholar Co-infection with other pathogens that are endemic to low-resource regions—eg, HIV, Mycobacterium tuberculosis, malaria parasites, and other parasites—might also increase the risk of developing infection-associated cancers. Finally, complex interactions might exist between behavioural, environmental, and infectious factors that predispose individuals to infection-related cancers to a greater extent in sub-Saharan Africa than in other regions. Therefore, elucidating the reasons for the geographical disparities in infection-related cancers is crucial to reducing the burden of these malignancies in settings with limited resources. Unique opportunities for prevention and treatment of infection-related cancers exist. Vaccination against hepatitis B virus and human papillomavirus, as well as screen-and-treat approaches for human papillomavirus, has already begun to decrease the incidence of cancers attributed to these infectious agents. With novel effective treatment regimens for hepatitis C, similar trends can be expected in the future if access is expanded worldwide. However, the four pathogens associated with the highest number of cancers—hepatitis C virus, Helicobacter pylori, Epstein-Barr virus, and human herpesvirus type 8—have no existing vaccines. Furthermore, a vaccine against HIV has enormous public health ramifications, not least of which is a reduction in cancer incidence. Thus, increased efforts and focus on vaccine development are of paramount importance. Other strategies to reduce the incidence of infection-related cancers are also worthy of consideration—eg, chemoprevention (ie, early initiation of antiretroviral therapy in HIV-infected individuals, eradication of H pylori, or prophylactic antiviral therapy in high-risk individuals) and behavioural or public health interventions to reduce incident cancer-associated infections. Finally, targeting the infectious cause of cancer might give rise to effective and inexpensive treatment strategies with minimal toxicity, such as the treatment of mucosal-associated lymphatic tumours with antibiotics.10Steinbach G Ford R Glober G et al.Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial.Ann Intern Med. 1999; 131: 88-95Crossref PubMed Scopus (224) Google Scholar With the availability of vaccines, screen-and-treat approaches, and effective drugs to treat hepatitis C virus, H pylori, and HIV infections, the question is no longer limited to what to do but now extends to how to implement. The expanding focus from basic research, drug development, and clinical trials that are historically concentrated in high-income countries, to basic, translational, and implementation science done in collaboration with centres in endemic areas, has the potential to both reduce the burden of infection-related cancers and shed light on presently unknown pathways in carcinogenesis. CC reports grants from Janssen Pharmaceuticals, personal fees from GlaxoSmithKline for being on the scientific advisory board, travel expenses and honoraria for lectures from Roche, and personal fees from TempTime outside the submitted work. CF declares no competing interests. Global burden of cancers attributable to infections in 2012: a synthetic analysisA large potential exists for reducing the burden of cancer caused by infections. Socioeconomic development is associated with a decrease in infection-associated cancers; however, to reduce the incidence of these cancers without delay, population-based vaccination and screen-and-treat programmes should be made accessible and available.
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