Cancers attributable to infection in the UK in 2010

For most infections, calculation of the population-attributable fraction (PAF) relies on the classic formula for population-attributable risk ( Cole and Macmahon, 1971 ): 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. IARC (2005) considers that there is convincing evidence that infection with HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 66 can lead to cervical cancer. For HPV 16, the evidence further supports a causal role in cancer of the vulva, vagina, penis, anus, oral cavity and oropharynx and a limited association with cancer of the larynx and periungual skin. HPV 18 also shows a limited association with cancer at most of these sites. Evidence for associations of HPV types of genus beta with squamous-cell carcinoma of the skin is limited for the general population. There is some evidence that HPVs are involved in squamous-cell carcinoma of the conjunctiva, but inadequate evidence for a role of HPVs in cancer of the esophagus, lung, colon, ovary, breast, prostate, urinary bladder, and nasal and sinonasal cavities. 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 ). Helicobacter pylori was classified as being carcinogenic for humans in 1994 ( IARC, 1994a ). It is considered to be causally associated with both carcinoma of the stomach and gastric lymphoma. 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 ). Estimated prevalence of Helicobacter pylori in the UK in 2000. The most satisfactory evidence on the magnitude of the risk is from prospective studies. Retrospective case–control studies are limited in observing H. pylori infection after the development of cancer. H. pylori tends to disappear as intestinal metaplasia and atrophy develop, so that prevalence of infection may be seriously under-estimated in cases, even if anti- H. pylori antibody is used as an indicator of infection. Several case–control studies nested within cohorts have now been published, in which infection is evaluated in cases and controls before the onset of disease. In a meta-analysis by the Helicobacter and Cancer Collaborative Group (2001) , including 12 prospective studies yielding 1228 gastric cancer cases, the OR for the association between H. pylori infection and the subsequent development of gastric cancer was 2.36 (95% CI 1.98–2.81). Analysing cancers of the gastric cardia, the most proximal portion of the stomach and non-cardia separately, they found no increase in risk for cardia cancers (OR 0.99), while the overall risk for non-cardia cancers was 2.97 (95% CI 2.34–3.77). The risk varied with the interval between sample collection and cancer diagnosis (as might be expected, if infection is progressively lost as gastric atrophy develops). The increase in risk was 5.9-fold (95% CI 3.4–10.3) for H. pylori positivity 10 years or more prior to diagnosis. The associations were not related to histological type of gastric cancer (intestinal vs diffuse) or sex. 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. One of the two large American cohort studies of H. pylori also examined the incidence of gastric NHL and found that these cases showed elevated titres of antibody to H. pylori ( Parsonnet et al, 1994 ). The relative risk was 6.3 (95% CI 2.0–19.9). Gastric NHL is rather a rare tumour, comprising about 5% of all NHL ( Newton et al, 1997 ). 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 . EBV is considered to be a group I carcinogen by IARC (1997) , with conclusive evidence with respect to carcinogenicity in Burkitt lymphoma, NHL in immunosuppressed subjects, sino-nasal angiocentric T-cell lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma. The evidence concerning other cancers for which an association with EBV has been demonstrated (lymphoepithelial carcinomas, gastric adenocarcinoma and smooth muscle tumours in immunosuppressed subjects) was considered to be inconclusive. Burkitt lymphoma : Burkitt lymphoma is a rare cancer in UK. There were an estimated 158 new cases in 2010. In North America and Europe, about one-fifth to one-third have demonstrable virus in tumour tissue, or elevated antibody titres to EBV ( Lenoir et al, 1984 ; Gutierrez et al, 1992 ). The numbers of EBV-attributable Burkitt lymphoma cases in UK is therefore about 39. 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. Case–control studies generally demonstrate higher titres of anti-EBV antibodies in cases of Hodgkin lymphoma than in controls ( Evans and Gutensohn, 1984 ). In a large prospective study, Mueller et al (1989) found that elevated antibody titres precede diagnosis by several years – the actual relative risks (2.6 and 3.7 for IgG and IgA capsid antigens, 4.0 for EBNA and 2.6 for early antigen (diffuse)) and prevalence of raised titres correspond to attributable risks of 30–45%. 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. The involvement of EBV in nasopharyngeal cancer (NPC) appears to be with undifferentiated carcinomas of the nasopharynx. In low-risk areas, about 10–25% of NPC is of type 1 (keratinising), which is less often infected. It is assumed that 90% of cases of the estimated 446 NPC cases occurring in the UK in 2010 are infected, a total of cases, or of all cancers or of the oral cavity and EBV is the most infection in the responsible for an estimated cases in 2010 of cancers), comprising cases of Hodgkin nasopharyngeal cancers and Burkitt lymphoma cases. The role of infection with the of and in the aetiology of cancer is well ( IARC, ). on the of a number of case–control and cohort an association between and NHL has been demonstrated ( et al, ; et al, ; and ). Prevalence of antigen positivity and antibodies in the serum of the general population of UK is as no results Age-specific prevalence is published for found to be positive are from becoming although these are individuals, with a prevalence much than the in the population. estimate of the prevalence of in adults based on a model all relevant was for England in ( ); this estimate had not been by the of 2010. data were assumed for with an estimate of prevalence at ages based on of samples in England and Wales in the ( et al, 2002 ). For the estimated population prevalence, based on of samples in England and Wales in 1996 ( et al, 1999 ), was used to the observed prevalence data from in England in ( ), and further to allow for the rather higher prevalence in in compared with those in England ( ). The estimated are shown in Figure 2 . Estimated and prevalence of of ( A ) and ( ) antibodies in the UK. The IARC the results of some cohort studies and case–control studies the association between for infection with HBV, and the risk of carcinoma. The cohort studies relative risk estimates of while the of case–control studies relative risk estimates between and of these studies were able to by and tobacco and the IARC overall as carcinogenic to A recent meta-analysis by et al found an for with a of for all studies and for the studies in as A relative risk of is assumed in the The magnitude of the risk of cancer associated with with as the results of studies using and or of In a meta-analysis of et al estimated the relative risk in subjects were as The more recent meta-analysis by et al found an of in studies from We assume a relative risk of for infection. Assuming relative risks of infection by these of and that infection by both and is very rare, estimate the fraction of cancers attributable to the two to be of This represents of cancers in the UK in 2010. At ( et al, ; et al, ; and ) have been to the of the between and The most recent of these ( and ) a rather estimate for the relative risk than the studies. However, as it considered all NHL and in age between cases and it is the most estimate. A recent the results of case–control studies ( et al, ) a result of the of and the estimated prevalence of infection in the UK in 2010 ( Figure 2 ), can estimate the fraction of NHL attributable to as of 11 In an IARC group that HIV was carcinogenic to an based on the between infection with the virus and two and NHL ( IARC, 1996 ). two with cancer of the cervix, are considered to be – that a with these cancers is considered to have AIDS ( 1992 ). increased risks for several other cancers have been The most convincing data from a of cohorts of subjects, the of cancers with the number in the general population. studies increased risks of several cancers, Hodgkin anal cancer, less cancers of the and ( et al, 1998 ; Frisch et al, 2001 ; et al, 2002 ). The by IARC (1997) considered that the evidence for a role of in the of was but as However, it is now generally accepted to be the cause of the ( and 2001 ). The of HIV is – allowing to and viral for to the of was a very rare cancer in the UK. et al the incidence in England and Wales in as in and of the increase in risk in subjects infected with HIV the risk in the general population ( et al, 1997 the incidence of was the of the AIDS to a of AIDS cases at some ( et al, 1993 ; et al, ). The of for HIV in adults has caused a in the incidence of in ( on HIV and 2000 ); in the for the incidence of in men in the cancer registries of the from 10 in to in ( et al, ). The estimated number of cases in UK in 2010 is might be to infection with on the in the ( et al, 1992 ), the number of cases was The difference is considered to be attributable to HIV while all cases of are attributable to infection with The increased frequency of NHL in AIDS was in ( et al, ). the elevated risk has been in studies in the and Europe ( et al, 1991 ; et al, 1991 ). About of AIDS cases with a lymphoma, but lymphomas may occur in to of AIDS cases at some all lymphomas in AIDS cases are of The cohort of et (1997) estimated the risk in AIDS to be about that in subjects. is highest for and undifferentiated Burkitt lymphomas lymphomas are more common in AIDS than ( et al, 1991 ), although it is because of the of lymphomas other lymphomas are not in ( et 1997 ). are more – but it be that this is because of EBV is in of AIDS-related lymphomas ( et al, 1993 ) and may have an role in ( IARC, 1996 , 1997 ). The frequency by lymphoma type – it is found in almost all lymphomas, of lymphomas and of The of in recent years has in a in the risk of NHL in it from in the to were ( on HIV and 2000 ). In the cohort studies that the relative risk of NHL in subjects the of is about ( et al, ; et al, ), and this is used to estimate the attributable The overall prevalence of HIV infection in the UK in was estimated to be in men and in women ( 2010 ). Prevalence in childhood and those is much and ( 2010 ; UK ). on these estimated and a relative risk of only cases of NHL in men and in women would have been attributable to HIV in 2010. The numbers but they are in with the numbers of cases based on observed incidence of NHL in subjects in recent years – for in the cohort in ( et al, ) and in in ( et al, ). With these cases of NHL would have in subjects in the compared with 11 expected, an of Hodgkin lymphoma : Several prospective studies that the risk of Hodgkin lymphoma is increased some in subjects ( et al, 1998 ; et al, 2001 ; et al, 2002 ). series including a higher frequency of the histological subtypes cellularity and and compared with the of of the HIV It is not most or all of these cases of Hodgkin lymphoma are related to EBV, all of which have been attributed to infection with this A calculation of cases has not been cancers : – most cancer of the cervix uteri and anal cancers – occur in with HIV infection and AIDS ( Frisch et al, 2000 ). In part, this may the factors associated with both – individuals are more to be infected by the other HIV may the of of immune infection with HPV or its in cells and therefore the development of squamous intraepithelial cancers have been attributed to infection with HIV infection has been found to be associated with an increased risk of in of cohorts of subjects in the USA ( and ; Frisch et al, 2001 ). With a relative risk of about of cases might be attributable to the prevalence of infection in the UK. only cases of cancer were registered in England in the number of attributable cases is In cases of and cases of NHL were caused by HIV in 2010. Of the cases, are attributed to infection with The evidence for the causal role of in T-cell is ( IARC, 1996 ). Prevalence of infection in UK is for ( ). it is 000 in men and 000 in women, with age. on the incidence of in England in cases would have been in the UK population. Table the quantification of cancers attributable to in the UK in 2010. The estimate is of all in men and of all in women. Of the total of the agents the are HPV cases, of all cancers), H. pylori cases, and EBV cases, The cancers for which an aetiology is most are cervix uteri cases in stomach and the upper aerodigestive tract pharynx and larynx –