Oncogene (2004) 23, 6341–6348 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc

Infections and immune factors in : the role of

Leo Kinlen*,1

1Cancer Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Oxford OX2 6HE, UK

An infective, mostly viral, basis has been found in an more than a dozen examples are established (see increasing number of different human . In all Table 1), mostly involving and all are rare cases, the is a rare response to the relevant responses to the relevant . This is often present infection, which is usually present in persistent form, and in persistent form and malignant transformation usually requiring specific cofactors for to develop. In requires additional (or co-) factors. The some cases, epidemiological evidence of infectivity pre- has basic importance in relation to infectious diseases ceded and promoted identification of the specific infection and in addition, the use of immunosuppressive drugs involved and even the discovery of the microbe itself, as in with organ transplants and the worldwide spread of Burkitt’s and cervix cancer. In other cases, the HIV infection have shown that immune impairment can discovery of the agent came first as in stomach and have major effects on cancer incidence. nasopharynx cancers, and epidemiology has been con- cerned mainly with confirming the relationship, measuring the size of the risk and identifying cofactors. Infection- Infection-linked cancers linked cancers include some of the commonest malig- nancies in certain large world regions, amounting to over Epidemiology has had a long-standing role in identify- 20% of all cancer in the developing countries. In addition ing evidence of infectivity, sometimes even before the to these cancers are others such as childhood leukaemia discovery of the relevant microbe. The following brief that show features indicative of an infective basis though review illustrates the different roles that epidemiological no underlying agent has been identified. Advances in this evidence can play in the discovery and study of field invite speculation about possible future discoveries in the origin of certain cancers, and also and how these might be promoted. However, in that something of the problems implicit in the subject. majority of cancers that are unrelated to sexual behaviour, there will be nothing even at the population level to suggest an infective basis because what is transmitted Burkitt’s lymphoma from one individual to another is not the neoplasm itself, The delineation of an unusual lymphoma in Africa but the underlying, often silent, infection to which the (Burkitt, 1962) was a landmark in cancer epidemiology. malignancy is an uncommon response. The increasing For not only was its association with high temperatures prevalence of immune impairment in human populations, and rainfall in lowland areas reminiscent of certain as a result of the use of immunosuppressive drugs with tropical infections, but shortly afterwards a new organ transplants and the spread of HIV infection, has herpesvirus, the Epstein–Barr (EBV), was identi- produced marked effects on cancer incidence in the fied in affected tissue (Epstein et al., 1964). This, the first affected groups including increases, of skin cancers, non- human tumour virus, turned out to be responsible for a Hodgkin’s lymphoma and Kaposi’s and to a ubiquitous and largely subclinical infection of infancy lesser extent of many other cancers, in some cases at least involving B lymphocytes. EBV infection therefore due to the release from immunological control of incipient contrasts markedly with the restricted distribution of infection-based . the endemic lymphoma (in Africa and Papua New Oncogene (2004) 23, 6341–6348. doi:10.1038/sj.onc.1207898 Guinea), indicating that the virus alone cannot explain Keywords: infections; immune impairment; cancer its occurrence. The combination of heavy EBV exposure with holo-endemic malarial infestation is now consid- ered important for the development of this tropical lymphoma. A sporadic form occurs in western countries but only in a variable minority of cases is EBV DNA found. Introduction

That human cancer can originate in an infection has Cervix cancer been known for less than 50 years, although in animals The early observation that uterine (mainly cervix) cancer this had been demonstrated some decades earlier. Now was rare in nuns (Rigoni-Stern, 1842) foreshadowed decades of epidemiological observations in the next *Correspondence: L Kinlen; E-mail: [email protected] century which overall pointed to the origin of the disease Infections and immune factors in cancer L Kinlen 6342 in a sexually transmitted infection, risk increasing with as shown in individual-based studies in high incidence the number of sexual partners, and also with that of areas of China and Africa (Ross et al., 1992; Qian et al., their partners. Initially -2 virus was 1994). A range of routes (including transplacental) for favoured as the candidate agent though case–control aflatoxin exposure is possible (Wild et al., 1991). There differences in antibody prevalence were never large. is a marked male excess (even in adolescence) in HBV- Later, a cohort of Czech HSV-2-positive women showed associated and some evidence that risk is no increase of cervix cancer (Vonka et al., 1984). modified by testosterone levels (Yu and Chen, 1993) and Evidence for the relevance of human papillomavirus perhaps by coinfection with virus (HCV) (HPV) notably advanced when zur Hausen and his co- (Donato et al., 1998). The protection already demon- workers isolated a new type (HPV 16) frombiopsy strated by against HBV holds promise for specimens from different regions (Durst et al., 1983). reducing the high liver cancer incidence in Africa and Since then abundant evidence has accumulated to China. indicate that virtually all cases of are Investigation of liver cancer cases that were negative due to a phylogenetically related subset of HPV types of for HBV led to the identification of the RNA HCV, which the most important are HPV 16, HPV 18 and which is entirely unrelated to HBV (Choo et al., 1989). HPV 45. These strains are transmitted by sexual This has been found to underlie many cases of liver intercourse, being responsible for mainly transient cancer in Japan where blood transfusions were until asymptomatic infection though in that small proportion recently a major source of infection, although sexual of women with persistent infection by these strains, transmission occurs in a minority. HCV is prevalent in cervical cancer may develop (IARC, 1995). Established Africa and Asia and has been estimated to cause cofactors include , oral contraceptives and high worldwide about 25% of all liver cancers, and alcohol parity (Castellsague and Munoz, 2003). Already several appears to be an important cofactor. vaccines are being tested that may help in long-term prevention of this cancer, whose large worldwide burden Nasopharyngeal cancer makes HPV the most important of the known human oncogenic infections (Parkin et al., 1999). Inclusion of sera frompatients with nasopharyngeal cancer (NPC) as controls for sera fromAfrican Burkitt’s Other Ano-genital cancers lymphoma cases first revealed the high antibody levels to the EBV capsid antigen (Old et al., 1966), which have An indirect link with the rare penis cancer was suggested since been a consistent finding in undifferentiated NPC. by the increased risk of cervix cancer in the wives of As with Burkitt’s lymphoma, EBV cannot explain this affected men as well as by other epidemiological cancer’s high incidence area (in southern China and SE correlations and has been confirmed by the high Asia); salted fish consumption, particularly at the time prevalence of HPV DNA in penile intraepithelial of weaning, appears to be an important cofactor. Such neoplasia (Demeter et al., 1993). HPV involvement has fish has been shown to contain nitroso compounds and also been found in anal and vulval cancers, with to induce EBV activity. There is also evidence for the evidence of HPV type 16 in anal cancer in several operation of socioeconomic and genetic factors. The case–control studies (IARC, 1995). status of EBV infection in this malignancy would obviously require revision if it is confirmed that such Primary liver cancer infection is an early secondary event in the malignant transformation of nasopharyngeal cells (Lin et al., That virus (HBV) might cause primary liver 1997). cancer was implicit in the association of hepatitis with chronic liver disease in which an increased incidence of Hodgkin’s disease this cancer was well known both clinically and epidemiologically. Convincing evidence, however, came Epidemiological hints that Hodgkins disease, at least in froma follow-up of maleTaiwanese civil servants in young adults, is infective in origin have a long history which the incidence of liver cancer among HBV carriers (MacMahon, 1966). Later, raised levels of EBV at entry to the study was 200-fold greater than in HBV- antibodies were found in stored serumcollected several negative men (Beasley et al., 1981), an estimate that years before the lymphoma developed and infectious became 100-fold with the larger number of cases found mononucleosis was shown to be a for the after longer follow-up (Beasley and Hwang, 1991). disease. It is estimated that more than 40% of new cases Other studies have found comparable increases of liver of Hodgkin’s disease in the world are EBV related cancer among chronic HBV carriers (IARC, 1994a). (Parkin et al., 1999). Persistent HBV infection is acquired mainly perinatally in China and in childhood in Africa. Aflatoxin, Adult T-cell leukaemia produced by certain Aspergillus fungi and a frequent contaminant of food staples, had originally been Only a few years after adult T-cell leukaemia/lymphoma considered a probable primary cause of liver cancer (ATL) was delineated in Japan as a new disease entity because of striking ecological correlations in Africa. It is (Uchiyama et al., 1977), its causative agent, human T- now recognized as a cofactor that modifies HBV effects, cell leukaemia virus type 1 (HTLV 1), was discovered

Oncogene Infections and immune factors in cancer L Kinlen 6343 (Poiesz et al., 1980). Both the virus and the disease occur et al., 1981) and this has since been confirmed both in mainly in Japan and the Caribbean. The virus is individuals with transplants and in certain inherited transmitted from mother to child in breast milk but immunodeficiency disorders which also show an in- also by direct contact, as between husband and wife. creased lymphoma incidence. Non- is also markedly increased in immunosuppressed HIV- infected people and in a proportion of cases EBV DNA is present in tumour cells. The unexpected discovery of Helicobacter pylori (War- ren and Marshall, 1983) and its role as the major cause of peptic ulcer led to finding a fairly consistent Oro- cancer association between stomach cancer and H. pylori Alcohol and tobacco have long been known as major antibody levels in stored serumsamplesin case–control risk factors for oral and pharyngeal cancers but evidence investigations ‘nested’ in cohort studies. A carcinogenic has mounted from recent case–control and cohort effect is also supported by the evidence for H. pylori as studies to indicate HPV type 16 involvement (Steenber- the likely cause of certain premalignant gastric lesions. gen et al., 1995; Smith et al., 1998; Franceschi et al., However, it is notable that the overall increase of risk of 2000; Gillison et al., 2000; Herrero et al., 2003). stomach cancer in such studies is only around 2.5-fold, suggesting that if this infection is causal some interac- Bladder cancer tion with another factor is likely (Danesh, 1999). The century-long suspicion of a link between schistoso- Kaposi’s sarcoma miasis infection and bladder cancer has been supported by several case–control studies in Egypt and elsewhere The enormously increased risk of Kaposi’s sarcoma in in Africa (IARC, 1994b; Vizcaino et al., 1994). The individuals with AIDS contracted homosexually in parasitic flatworm( Schistosoma haematobium) of aqua- contrast to intravenous drug abuse pointed to a basis tic snails can also infect people frominfested freshwater in a sexually transmitted infection (Beral et al., 1990). if cutaneous penetration occurs, reaching the bladder by The agent has now been identified as human herpes subsequent vascular spread. virus 8 (HHV8) or Kaposi’s sarcoma-associated herpes virus (KSHV) (Chang et al., 1994). The global distribu- tion of this malignancy broadly reflects the high prevalence areas for the virus, rare in non-Mediterra- Infection of the biliary systemby the liver fluke nean countries in the West and common in Africa. In Opisthorcis viverrini has been found to explain the high the West, infection in gay men is related to the number incidence in north-east Thailand of the rare cholangio- of sexual partners, but in Africa other routes of carcinoma in both its intra- and extrahepatic forms transmission exist. (IARC, 1994b).

Skin cancer in epidermodysplasia verruciformis Other malignancies The rare genetically determined epidermodysplasia Case series have suggested a much increased incidence of verruciformis (EV) is associated with a greatly increased leiomyosarcoma following HIV infection or an organ incidence of squamous cell skin cancer. An early finding transplant in children (though not in adults) and EBV in the molecular biology of human oncogenic viruses DNA has been identified in tumour tissue from affected was for HPV involvement in these cancers (Orth et al., children. H. pylori has been reported frommostcases of 1978). Evidence has continued to mount particularly for the gastric non-Hodgkin’s derived from HPV 5 and 8, types which in the general population are mucosa-associated lymphoid tissue (MALT), and many abundant and asymptomatic. In addition to the under- respond well to antibiotic therapy. However, causation lying genetic fault, sunlight is an important factor in of these tumours by the associated agent is not yet these skin cancers in EV. These three factors might be established. Similarly, the evidence for S. japonicum seen as a model for the complex causation of other infection in colorectal and liver cancers is not yet cancers as well. persuasive of causality, although the associated color- ectal cancers seemoften to occur at strikingly young Transplant (and related) lymphomas ages in Japan and China (Newton et al., 1999b). A marked increase in the incidence of non-Hodgkin’s lymphoma, often involving the brain, was an early observation in transplant recipients. The short interval Unidentified infective causes of cancer after transplantation in which this excess can first be detected pointed to a causation very different from Given the difficulty of identifying new viruses, it is likely chemically induced cancers typified by lung cancer, and that other cancers with an infective basis exist. In some an already-present virus seemed likely (Kinlen et al., of the cancers considered above, it was epidemiological 1979). Shortly afterwards evidence was found for EBV evidence of infectivity that encouraged the finally as the underlying agent (Crawford et al., 1981; Hanto successful search to identify the underlying agent, as in

Oncogene Infections and immune factors in cancer L Kinlen 6344 Table 1 Malignancies linked to specific infective agents these are more prevalent in rural areas because of the Site or type of cancer Infective agent reduced opportunities for contacts, it was argued that a localized epidemic of an underlying infection would be Primary liver cancer HBV promoted by large-scale rural–urban population mixing Primary liver cancer HCV (i.e. by the implied mixing of susceptible and infected Burkitt’s lymphoma EBV Cervix cancer HPV types 16, 18, etc. individuals, thereby producing increases of its complica- Penis cancer HPV tion, childhood leukaemia (Kinlen, 1988). Such excesses Adult T-cell leukaemia HLTV 1 have been found in all the examples of marked rural– Kaposi’s sarcoma HHV8 urban mixing in Britain in the past 60 years, including Nasopharynx cancer EBV rural new towns (Kinlen et al., 1990), wartime evacua- Stomach cancer H. pylori Hodgkin’s disease EBV tion of children to rural areas (Kinlen and John, 1994), Post-transplant lymphoma EBV increases of national servicemen in rural areas (Kinlen Oro-pharynx cancer HPV type 16–18 and Hudson, 1991), areas around large rural (non- Bladder cancer S. haematobium nuclear) construction sites (Kinlen et al., 1995), rural Cholangiocarcinoma O. viverrini Squamous cell skin cancer in EVa HPV types 5 and 8 Scottish communities where a large proportion of men had worked away fromhomein the North Sea oil aEpidermodysplasia verruciformis industry (Kinlen et al., 1993) and in wartime Orkney and Shetland where large numbers of servicemen were stationed (Kinlen and Balkwill, 2001). The incomers in Burkitt’s lymphoma, cervix cancer and Kaposi’s sarco- some of these rural situations, including the last three, ma; in others, it was the microbiological advance that consisted only of adults, indicating that adults as well as came first, as in adult T-cell leukaemia and stomach children can be involved in the chain of transmission. cancer. Excepting the highly unusual geographical Dickinson and Parker (1999) were able to account distribution of Burkitt’s lymphoma, it is notable that statistically for the Seascale excess in a model of the the strongest epidemiological pointers have involved effect of population mixing upon childhood leukaemia sexual transmission and the explanation is not hard to risk using information on births in Cumbrian wards find: with malignancies that are rare responses to an other than Seascale. This, together with the earlier work, infection that is not sexually transmitted, there will be led Doll (1999) to conclude that the epidemiological nothing even at the population level to suggest infection. evidence for an infective basis in the disease was For the underlying infection would have usually been compelling. Observations made outside Britain have transmitted from someone whose infection was uncom- confirmed the importance of unusual patterns of contact plicated by the cancer. If certain approaches in child- (Kinlen and Petridou, 1995; Petridou et al., 1996; hood leukaemia (see below) have wider application, then Alexander et al., 1997, 1999; Koushik et al., 2001; evidence of infectivity in such cases may not depend Boutou et al., 2002) and most recently in the small desert entirely upon microbiology making the first and crucial town of Fallon in Nevada where a large increase of cases advance. of childhood leukaemia occurred in 2000 at the same An indication of the variety of types of evidence in the time as the intake of trainees stationed temporarily at absence of any specific agent that points to, or at least the nearby airbase reached a peak of 55 000 froman raises the possibility of, an infectious cause is given by earlier level of 20 000/year (Kinlen and Doll, 2004). the following four examples. Underlying infection in childhood leukaemia is also supported by a lower risk reported when older siblings Childhood leukaemia are present (high birth order) or after early day care. Findings with respect to the former have not been Suspicion of an infective basis in childhood leukaemia is consistent though it is notable that a marked birth order long standing, and has been encouraged by the effect was found in one of the largest studies (Dockerty discovery of the viruses underlying several animal et al., 2001). Evidence of protection fromearly exposure leukaemias. The disease is not contagious (marked to day care has been more consistent (Petridou et al., space–time clustering is absent) so, if infective, it must 1993; Infante-Rivard et al., 2000; Rosenbaum et al., belong to that large category of disorders that are rare 2000; Ma et al., 2002; Jourdan-Da Silva et al., 2004). responses to infection, which here is unidentified though Such effects would be analogous to the immunity left clearly widespread. Excesses of childhood leukaemia after early exposure to the well-known infections of occurred in Seascale near the Sellafield nuclear installa- childhood including virus infection in which the tion in north-west England and in Thurso near the likelihood of clinical disease is influenced by age at nuclear site at Dounreay in Caithness, northern Scot- exposure. land which could not be explained in terms of radiation exposure. This led to the population mixing (infective) Conjunctival cancer hypothesis, for both those areas were remote and isolated and had experienced highly unusual population The rare squamous cell conjunctival cancer that is movements (Kinlen, 1995, 2000). From the well- associated with heavy sun exposure has increased in established premises that epidemics are fuelled by the incidence in sub-Saharan Africa coincident with the availability of sufficient susceptible individuals and that spread of HIV infection; a marked excess has also been

Oncogene Infections and immune factors in cancer L Kinlen 6345 demonstrated in infected individuals (Newton, 1996). of EBV involvement in these lymphomas. The links Some evidence has been reported of the risk being between these (or related) malignancies and infection associated with certain HPV types but this has not been suggested therefore that immune impairment favoured a consistent finding and further work is in progress. of infective origin, rather than all cancers as Burnet’s hypothesis had implied. The original concept of Skin cancer in transplant recipients immunosurveillance was also apparently undermined by finding that athymic nude mice did not experience an The involvement of HPV in the skin cancers that increased incidence of cancer, although recent observa- complicate epidermodysplasia verruciformis has stimu- tions have called this inference into question (Shankaran lated investigation of HPV in the (markedly increased) et al., 2001). squamous cell skin cancers among transplant recipients Recent studies of transplant recipients with larger with some positive findings; causation remains to be numbers and more prolonged follow-up (Birkeland established. et al., 1995; Adami et al., 2003) have shown that the range of malignancies showing excesses among trans- Breast cancer plant recipients is broader than found previously. Table 2 presents findings froma recent study in Sweden The recognition that mammary tumours in mice are (Adami et al., 2003) showing the most striking excesses caused by the murine mammary tumour virus, with observed (Po0.01) as well as the risks for those cancers transmission, mainly in milk, led to laboratory and that are commonest in the general Swedish population. epidemiological searches for evidence of a correspond- It is striking that significant excesses are shown for most ing agent in human breast cancer, but with negative sites other than nervous systemand the hormone-related results. The fact that these murine tumours are cancers of breast, ovary and prostate, although the oestrogen-sensitive and that viral transmission can also magnitude of their increased risks is much smaller than occur by direct contact may still offer useful parallels in those for lymphomas, skin cancer and Kaposi’s sarco- speculations about the human disease. This is particu- ma. Similar findings have been obtained in a large larly the case since as an uncommon response to a ongoing UK study of renal transplant recipients (Kinlen nonsexually transmitted agent, there would be nothing and Balkwill, in preparation). It is not clear, however, obviously to suggest infection. Over the past decade, whether this wide range of excesses indicates that more laboratory reports offering somewhat variable evidence cancers are infective in origin than is usually considered of altered EBV gene expression in this disease (Labrec- or that Thomas and Burnet’s original hypothesis is in que et al., 1995; Magrath and Bhatia, 1999; Xue et al., large part correct. 2003) have, perhaps not surprisingly, received little The worldwide epidemic of HIV infection has epidemiological attention, although an increased risk provided further scope for examining the effects of has recently been found with increasing age of self- immune impairment in cancer aetiology, although the reported (Yasui et al., 2001). specific cancers showing excesses appear to differ somewhat from those in transplant patients; for example, an excess of skin cancer has not been a Immune impairment consistent finding. However, as in transplant recipients,

Under the immunosurveillance hypothesis of Thomas Table 2 Major risks following organ transplantation in Sweden, (1959) and Macfarlane Burnet (1970), immune impair- a ment should promote cancer development, for the including risks for common cancers concept holds that a healthy immune system eliminated Site No. of cases Relative risk P-value aberrant clones that would otherwise formthe basis for Lip 40 53.3 *** clinical cancer. The development of organ transplanta- Oral cavity 11 5.5 *** tion and associated immunosuppressive therapy in the Stomach 12 2.3 * 1960s provided a timely opportunity for this view to be Colon 25 1.9 *** tested. The first prospective studies of renal transplant Rectum14 1.9 * Lung 24 1.7 * recipients did indeed show excesses of cancer but, at that Breast 24 1.0 NS time, the sites involved were far from being representa- Cervix in situ 52 1.3 NS tive of the important cancers in most human groups Ovary 9 2.0 NS (Hoover and Fraumeni, 1973; Kinlen et al., 1990) and and vagina 11 20.9 *** included non-Hodgkin’s lymphoma (often with cerebral Prostate 20 1.1 NS Kidney 28 4.9 *** involvement), squamous cell skin cancer, primary liver Bladder 20 2.3 ** cancer and Kaposi’s sarcoma. The excess of non- 14 1.8 0.06 Hodgkin’s lymphoma was remarkable in being detect- Skin (squamous cell) 278 56.2 *** able even within 6 months of transplantation, very Brain 7 1.0 NS Non-Hodgkin’s lymphoma 45 6.0 *** different fromthe long latent interval of cancers caused All cancers 692 4.0 *** by chemicals, typified by tobacco smoking. This made transformation by an already-present virus seem likely aTaken as those with an expected value of 4 or greater *Po0.05; which has since been confirmed by the consistent finding **Po0.01; ***Po0.001

Oncogene Infections and immune factors in cancer L Kinlen 6346 the malignancies showing the most marked increases in types of ALL (Jourdan-Da Silva et al., 2004). A incidence include some of those that are known to be declining risk with increasing birth order would also linked to viruses such as Kaposi’s sarcoma, non- point to an effect of early infective exposures in the Hodgkins lymphoma, Hodgkin’s disease and cervix household and, although not a consistent finding, was cancer. Squamous cell conjunctival cancer shows a found by a recent large study (Dockerty et al., 2001). greatly increased incidence in African AIDS victims but The Greaves hypothesis represents a departure from has not been definitely linked to a specific virus (Newton the virtual synonymy of infectivity with the actions et al., 1999a; Boschoff and Weiss, 2002). of specific microbes and if correct, would obviously make searching for a specific underlying agent in c.ALL futile. However, protective effects of early infective Immunostimulation exposures would also be consistent with age influencing the clinical response of specific (e.g. polio virus) The possibility of chronic antigenic stimulation as a infection and subsequent immunity, for as yet there is cause of myeloma has often been considered but little no evidence that they are due to infections acting support has emerged from epidemiological studies nonspecifically. (Herrington et al., 1996). Immunostimulation by neo- natal BCG vaccination in Quebec was claimed to have markedly reduced childhood leukaemia risk, but no Conclusion differences could be detected when leukaemia mortality in Quebec was formally compared with that in the With the discovery of more virus-caused cancers and of Canadian provinces without such a BCG policy, nor the role of cofactors, it is difficult to overlook certain between Glasgow and the rest of Scotland where a similarities with the implications of the apparently similar contrast existed (Kinlen and Pike, 1971). Studies discredited viral theory of cancer causation that was of BCG elsewhere and of other immunizations overall promoted by Huebner and others in the US National have not suggested any consistent effect on childhood Cancer Institute’s 1970s special virus cancer pro- leukaemia incidence (Little, 1999). gramme. Indeed it may be salutary to reflect that even Delayed antigenic stimulation has been proposed as a the most firmly established chemical carcinogens such as cause of common acute lymphoblastic leukaemia tobacco smoking and oestrogens do not exclude their (c.ALL) in the childhood peak years of ages 2–6. interaction with unidentified viruses. It has been Greaves (1988) suggested that infections, to which estimated that infections cause around 15% of the modern life tends to delay exposure until after infancy, world’s cancer and over 20% of that in the developing induced proliferation and hence mutation in non-fully countries (Parkin et al., 1999) and future findings could differentiated, vulnerable lymphocytes. Several studies well result in an appreciable increase in this proportion: have found evidence of protective effects using early for recent history has underlined how unexpected day care as surrogates for early infection (Petridou discoveries may still await workers in the difficult field et al., 1993; Infante-Rivard et al., 2000; Rosenbaum of infective oncogenesis. It is to be hoped that despite et al., 2000; Ma et al., 2002; Jourdan-Da Silva et al., the pressing demands of HIV research, epidemiological 2004), although when c.ALL was examined separately, clues to infective causes of various cancers will never- it did not show the effect more markedly than did other theless be pursued.

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