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The infectious agents that have been identified as definitely or probably carcinogenic to humans (Groups 1 and 2A) in the International Agency for Research on Cancer (IARC) monograph series are shown in Table 1. They include hepatitis B (HBV) and C (HCV) viruses, human papillomaviruses (HPV), human immunodeficiency virus (HIV) and T-lymphotropic virus type-1 (HTLV-1), Epstein–Barr virus (EBV) and human herpesvirus 8 (HHV8), and the bacterium Helicobacter pylori. In addition to these associations, there is substantial evidence for a causative relationship between chronic infection with hepatitis C virus (HCV) and non-Hodgkin lymphoma (NHL), an association that has been the subject of several recent systematic reviews (Gisbert et al, 2003; Matsuo et al, 2004; dal Maso and Franceschi, 2006). where r represents the relative risk of exposure, and p its prevalence in the population. The formula results in a proportion that is applied to the total number of incident cases in the UK population, to obtain the number of cases that can theoretically be attributed to the factor in that population (PAF). Its application requires identification of data on the prevalence of the exposure to the ‘causative’ agents in the UK population, as well as the corresponding relative risks. This method is used to estimate the number of cancers due to HBV, HCV, H. pylori and HIV (NHL). For EBV, the prevalence of relevant infection is hard to define, as the virus infects almost everyone in childhood or adolescence and persists in latent form in B-lymphocytes throughout life. Clearly, agents other than EBV are essential co-factors in carcinogenesis, and EBV-attributable cancers are defined as those in which EBV-DNA can be demonstrated in tumour cells. For the oncogenic HPVs, it is generally accepted that almost all cancers of the cervix uteri are the result of infection (Walboomers et al, 1999), so the AF is 100%. At other sites, the prevalence of infection in normal subjects is hard to define, so use of the classic Cole–MacMahon formula is inappropriate; as for EBV, the HPV-attributable cancers are defined as those in which HPV-DNA can be demonstrated in tumour cells. With respect to cancer of the cervix, oncogenic HPV may be detected by PCR in virtually all cases of cervix cancer, and it is generally accepted that the virus is necessary for development of cancer, and that all cases of this cancer can be ‘attributed’ to infection (Walboomers et al, 1999). With respect to squamous-cell cancers of the vulva and vagina, carcinoma of the penis, and anal cancer, published studies do not allow quantification of relative risk and infection prevalence, because they are generally small in size, and usually do not include comparable measurement of prevalence of infection at these sites in normal subjects. In order to estimate attributable fractions, therefore, approximate estimates of the proportion of cancer cases infected with HPV in various series are used. The prevalence of HPV in vaginal cancer is about 60–65% in studies using PCR methodology (Daling et al, 2002; IARC, 2005); an overall HPV prevalence of 63% is assumed. About 20–50% of vulvar cancers contain oncogenic HPV DNA (Madeleine et al, 1997; Herrero and Munoz, 1999), but only the basaloid and warty type that tends to be associated with vulvar intraepithelial neoplasia is caused by HPV infection (prevalence 75–100%), and only 2–23% of the keratinizing carcinomas harbour HPV (Trimble et al, 1996); an overall HPV prevalence of 40% is assumed. For anal cancer, in a large series of cases from Denmark and Sweden, 95% and 83% of cancers involving the anal canal in women and men, respectively, were positive for oncogenic HPV (Frisch et al, 1999), and an AF of 90% is assumed. For penile cancer, HPV DNA was found in 30% of 71 cases of penile cancer from Brazil (Bezerra et al, 2001) and in 42% of 148 cases from the USA and Paraguay (Rubin et al, 2001); the AF is assumed to be 40%. HPV has a role in the aetiology of a fraction of cancers of the oral cavity and pharynx (Shah, 1998), although the major risk factors are tobacco and alcohol. A review of more than 5000 tumours of the upper aerodigestive tract (Kreimer et al, 2005a) found that prevalence of HPV DNA in specimens from Europe was 16.0% (95% CI, 13.4–18.8) for oral cancers, 28.2% (95% CI, 24.4–32.2) for tumours of the oro-pharynx and 21.3% in squamous cell carcinomas (SCCs) of the larynx. However, HPV may not be of aetiological relevance in all such cases. Van Houten et al (2001) found that only 45% of DNA-positive cases showed E6 mRNA expression, indicative of viral activity. Kreimer et al (2005b) observed that about 50% of head and neck cancers had a high viral load of HPV, and serologic antibodies to HPV16 virus-like particles and HPV16 E6 and E7 proteins were detected in most of these cases. We assume therefore that 8% oral cancers, 14% oropharyngeal cancers and 10.6% laryngeal cancers are HPV-related. HPV (any type) is estimated to be responsible for 5088 cancers occurring in the UK in 2010 (1.6% of all cancers), comprising 2691 cervix cancers, 1685 cases of ano-genital cancer and 712 cases of upper aerodigestive tract cancer (Table 2). Surveys of H. pylori show that prevalence gradually increases with age. Several studies have suggested that this represents a birth-cohort effect, with infection becoming progressively less common in recent generations (Banatvala et al, 1993; Kosunen et al, 1997; Roosendaal et al, 1997). In the UK the most comprehensive data on prevalence derive from the serological surveys of 10 000 serum samples collected in England and Wales in 1986 and 1996 (Vyse et al, 2002). Prevalence was related to decade of birth and increased from 4% in those born during the 1980s to 30% in those born before 1940; analysis by decade of birth showed no significant difference between samples collected in 1986 and 1996. Estimated prevalence of active infection varied by region and was highest in London. We estimated prevalence in the UK population in 2000 from the data provided by Vyse et al (2002), assuming that prevalence in Scotland and Northern Ireland was the same as that observed in the North of England (Figure 1). The proportion of gastric cancer cases occurring at the cardia, compared with elsewhere in the stomach, can be estimated from cancer registry data from England (2007), and from the results of 11 registries throughout the UK in 1998–2005 (Curado et al, 2007). In both sets, a variable proportion of gastric cancer cases (40–65%) are registered without specification of subsite. However, fitting a linear regression model of the proportion of cardia cancers vs the proportion of unspecified registrations suggests that mis-specification of site is more or less random. The predicted proportion of cardia cancers (with zero non-specification) is 51.9% in men and 38.9% in women. Age-specific proportions in the UK were estimated based on the distribution by age in England (2007). With a relative risk of 5.9 and prevalence of infection in 2000 (10 years earlier) as shown in Figure 1, the attributable fraction of non-cardia gastric cancer cases in 2010 is 61% in men and 59% in women. This represents 2231 cases, 29.2% of all stomach cancers in men and 36.0% in women, or 0.7% of all cancers. Assuming that 5% of NHL cases in UK are localised to the stomach, there were about 580 new cases in 2010. With a relative risk of 6, and the estimated prevalence of infection in 2000 (Figure 1), 2.8% of NHL cases (327) would be attributable to H. pylori. Other NHL: EBV can cause lymphoproliferative diseases in individuals with immune dysfunction (Lenoir and Delecluse, 1989). Lymphomas arising in immunocompromised individuals are relatively rare, except in the case of AIDS, some of which are associated with EBV. The proportion of AIDS-related lymphomas is estimated in the context of HIV-related cancers (below). The proportion of NHLs that occur in immunocompromised individuals, excluding AIDS (hereditary, syndromes, iatrogenic), or are cases of the rare EBV-associated sino-nasal angiocentric T-cell lymphoma, is impossible to estimate. It must be a very small (<1%) fraction of NHLs, so there is no numerical allowance for these cases in the estimates. Sensitive techniques are able to detect EBV nucleic acids in 25–50% of Hodgkin lymphomas, where it is located in the Reed–Sternberg cells (Weiss et al, 1989; Armstrong et al, 1992). The association with EBV appears to depend upon age. In the childhood age range about 80% of cases are EBV positive (Weinreb et al, 1996), whereas in young adults the proportion is about 15% (Jarrett et al, 1991). In older age groups, EBV positivity appears to be relatively high (70–75%) (Jarrett et al, 1991; Gledhill et al, 1991). In part, this pattern is determined by the frequency of different histological subtypes of Hodgkin lymphoma. The mixed cellularity subtype predominates in childhood, while the nodular sclerosing subtype accounts for the marked peak in young adults. The frequency of EBV positivity is much greater (5–15-fold) in mixed cellularity than in nodular sclerosing Hodgkin lymphoma. Nevertheless, it seems that, even allowing for cell type, age (more childhood cases are EBV positive) and level of socio-economic development are independent predictors of the association (Glaser et al, 1997). For the purposes of estimation, the attributable fraction at ages 0–14 is taken to be 80%, 20% at ages 15–44, and 70% at ages >45. Of the UK total of 1709 new cases in 2010, 773, or 45.2% of the total, are estimated to be EBV related. Prevalence of hepatitis B surface antigen (HBsAg) positivity and HCV antibodies in the serum of the general population of UK is unknown, as no true random survey results exist. Age-specific prevalence is published for first-time blood donors (subjects found to be positive are obviously excluded from becoming repeat donors), although these are healthy individuals, with a prevalence much lower than the average in the population. An estimate of the prevalence of hepatitis C in adults (aged 15–59), based on a model incorporating all relevant samples, was made for England in 2003 (HPA, 2006); this estimate had not been updated by the end of 2010. These data were assumed for UK, with an estimate of prevalence at ages >60 based on sero-surveys of laboratory samples in England and Wales in the 1990s (Balogun et al, 2002). For hepatitis B, the estimated population prevalence, based on sero-surveys of laboratory samples in England and Wales in 1996 (Gay et al, 1999), was used to adjust the observed age–sex-specific prevalence data from blood donors in England in 1995–2008 (HPA, 2009), and further adjusted upwards, to allow for the rather higher prevalence in blood donors in UK, compared with those in England (HPA, 2009). The estimated prevalences are shown in Figure 2. The magnitude of the risk of liver cancer associated with chronic ‘infection’ with HCV became evident as the results of studies using second- and third-generation anti-HCV ELISA tests or detection of HCV RNA (by reverse transcription polymerase chain reaction) became available. In a meta-analysis of studies, Donato et al (1998) estimated the relative risk in HCV antibody-positive subjects who were HBsAg negative as 17.3. The more recent meta-analysis by Cho et al (2011) found an odds ratio of 23.8 in seven studies from low-prevalence countries. We assume a relative risk of 20 for HCV infection. Assuming relative risks of chronic infection by these viruses of 20, and that joint infection by both HBV and HCV is very rare, we estimate the fraction of liver cancers attributable to the two viruses to be just 15.9% (567 of 3568 cases). This represents 0.18% of cancers in the UK in 2010. The evaluation by IARC (1997) considered that the evidence for a role of KSHV/HHV8 in the causation of KS was ‘compelling, but as yet limited’. However, it is now generally accepted to be the principal cause of the disease (Boshoff and Weiss, 2001). The effect of HIV is probably through immunosuppression – allowing HHV-8 to escape control and thereby increasing viral load, for example. Because of the enormous increase in risk in subjects infected with HIV (1000–5000 times the risk in the general population (Serraino et al, 1997)), the increasing incidence of KS was the first obvious manifestation of the AIDS epidemic. Before 1990, up to a third of AIDS cases developed KS at some point (Hoover et al, 1993; Lundgren et al, 1995). The introduction of antiretroviral therapy (HAART) for treating HIV in adults has caused a decline in the incidence of KS in Western countries (International Collaboration on HIV and Cancer, 2000); in the USA, for example, the incidence of KS in men aged 20–54 in the cancer registries of the SEER program fell from 17.2 per 105 in 1990–1 to 2.4 in 2000–2001 (Ries et al, 2004). The estimated number of KS cases in UK in 2010 is 172. All might be ascribed to infection with HHV-8. Based on the rates in the pre-AIDS era (Grulich et al, 1992), the number of cases expected was 10. The difference (162 cases) is considered to be attributable to HIV infection, while all cases of KS are attributable to infection with HHV-8. EBV is present in two-thirds of AIDS-related lymphomas (Hamilton–Dutoit et al, 1993) and may have an important role in lymphomagenesis (IARC, 1996, 1997). The frequency varies by lymphoma type – it is found in almost all CNS lymphomas, 70–80% of immunoblastic lymphomas and 30–40% of small-cell/Burkitt-type lymphomas. The availability of HAART in recent years has resulted in a decline in the risk of NHL in HIV-infected individuals; it fell from 0.62% per year in the pre-HAART era (1992–1996) to 0.36% when HAART regimens were widely available (1996–1999) (International Collaboration on HIV and Cancer, 2000). In the USA, cohort studies suggest that the relative risk of NHL in HIV-positive subjects since the introduction of HAART is about 6.5 (Hessol et al, 2004; Engels et al, 2008), and this figure is used to estimate the attributable fraction. The overall prevalence of HIV infection in the UK in 2009 was estimated to be 2.89 per 1000 in men aged 15–59 and 1.46 per 1000 in women (HPA, 2010). Prevalence in childhood and those over 60 is much lower: 0.09 and 0.46 per 1000, respectively (HPA, 2010; UK CGHSS, 2006). Based on these estimated prevalences, and a relative risk of 6.5, only 52 cases of NHL in men and 16 in women (69 total) would have been attributable to HIV in 2010. The numbers seem small, but they are broadly in line with the numbers of cases expected based on observed incidence rates of NHL in HIV-positive subjects in recent years – for example, 1.8 per 1000 in the Swiss cohort in 2002–6 (Polesel et al, 2008) and 0.97 in three US states in 1996–2002 (Engels et al, 2008). With these rates, 120 cases of NHL would have occurred in HIV-positive subjects in the UK, compared with 11 expected, an excess of 109. HPV-associated cancers: HPV-associated malignancies – most notably cancer of the cervix uteri and anal cancers – occur frequently in patients with HIV infection and AIDS (Frisch et al, 2000). In part, this may simply reflect the lifestyle factors associated with both infections – HIV-positive individuals are more likely to be infected by HPV. On the other hand, HIV may alter the natural history of HPV-associated oncogenesis through loss of immune control, facilitating infection with HPV or enhancing its persistence in cells and therefore increasing the development of squamous intraepithelial lesions (SIL). These cancers have already been attributed to infection with HPV. HIV infection has been found to be associated with an increased risk of conjunctival SCC in follow-up of cohorts of HIV-positive subjects in the USA (Goedert and Coté, 1995; Frisch et al, 2001). With a relative risk of 10, about 1% of cases might be attributable to HIV, given the prevalence of infection in the UK. As only 23 cases of conjunctival cancer were registered in England in 2007, the number of attributable cases is ignored. The cancers for which an infectious aetiology is most important are cervix uteri (2691 cases in 2010), stomach (2231) and the upper aerodigestive tract (mouth, pharynx and larynx – 1113 cases). Worldwide, 17.8% of all cancers are attributable to infections (Parkin, 2006), with a higher percentage in developing countries (26.3%), and an average of 7.7% in developed countries reflecting the higher prevalence of infection with the major causative agents (hepatitis viruses, HPV, H. pylori, HIV). The proportion in the UK is around half of the average for developed countries, and very similar to the estimate (3.5%) for the Netherlands (van Lier et al, 2008). The results are dependent on the assumptions made about relative risk, and accuracy of the estimates of prevalence of infection in the general population. For some of the associations – especially in relation to HPV and anogenital cancers – the estimate of attributable fraction was based on the proportion of tumours in which the virus (as viral DNA) could be detected. The reason is mainly that prevalence of infection in the same tissues of normal individuals is usually unknown. This may overestimate attributable fractions, by including some cancer cases in which the presence of the virus was coincidental, without, for example, expressing viral oncoproteins. The estimate of HPV-attributable cancers of the oral cavity, pharynx and larynx attempts to compensate for this, by estimating the number of aetiologically relevant infections (expressing E6 and E7 proteins, for example). The estimate of infection-attributable cancer is a conservative one. Some other associations between infections and human cancers, for which there is reasonable evidence for causality, have not been taken into account. EBV has been detected in several types of cancer, other than those attributed to it in this analysis, with the most suggestive evidence implicating it in the aetiology of gastric cancer (Takada, 2002; Herrmann and Niedobitek, 2003). Chlamydia trachomatis infection has been shown to increase the risk of developing SCC of the cervix (Smith et al, 2004). In any case, no case of cancer has been attributed to more than one infectious agent, so that the numbers of infection-attributable cases can be calculated for different populations. Thus, for example, the risk of cancer of the cervix uteri may be increased by HIV infection (Frisch et al, 2001) as well as C. trachomatis, but as all cases are attributed to HPV, none are included as HIV-related cancers. In addition, the estimates of relative risk for those associations accepted as causal that have been used in the calculations are deliberately modest. For example, the relative risk of liver cancer due to infection with hepatitis B is based on measurement of serum HBsAg. However, viral DNA can be found in many liver cancers without evidence of infection based on HBs antigenaemia or antibody to HCV (Paterlini et al, 1990). The relative risk of non-cardia gastric cancer in relation to infection with H. pylori that was used (5.9) may also be too modest; more sensitive techniques for estimating the presence of H. pylori (for example, by detecting bacterial DNA) have much higher relative risks (Mitchell et al, 2008), but as the prevalence estimates are based on the presence of anti-H. pylori antibody, we use the relative risk estimates based on the same techniques. Accepting that all non-cardia gastric cancers are caused by infection (H. pylori and/or EBV) as well as 10% of NHL are caused by HCV (independent of HIV) would not, however, greatly change the overall estimate. See acknowledgements on page Si. The author declares no conflict of interest.

11. Cancers attributable to infection in the UK in 2010