While the discovery that viruses can cause tumors in animals traces back to 1 century ago (1
), the implication of microbial and parasitic diseases in the causation of human cancers has been demonstrated more recently. The burden of infection-associated cancers depends on a variety of factors. An important one is the geographic area, since certain chronic viral and bacterial infections and trematode infestations have a greater epidemiological impact in developing countries, as compared with developed countries, where only 16% of the world population resides. This circumstance is due to the higher endemicity, in developing countries, of infectious and parasitic diseases posing carcinogenic risks and to the lower availability of both preventive and therapeutic tools aimed at curing the disease or at avoiding its chronic evolution.
The proportions of cancer deaths attributable to viral and bacterial infections and to parasitic diseases were tentatively estimated by Doll et al.
) to be 10% in the USA in 1981 and by Doll to be 10–20% in UK in 1998 (3
). Pisani et al.
) estimated that 15.6% (1
000 cases) of the worldwide incidence of cancers in 1990 could be attributed either to hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein–Barr virus, human T-cell lymphothropic (T-cell leukaemia/lymphoma) virus (HTLV)-1, human immunodeficiency virus (HIV), Helicobacter pylori
, schistosomes or liver flukes. These data were updated in 2006 by Parkin (5
) who, based on the evidence of the strength of association and the prevalence of infection in different geographic areas, estimated that the total infection-attributable cancer in the year 2002 was 1.9 million cases, which accounted for 17.8% of all cancers in the world. By preventing cancer-associated infectious diseases, there would be 26.3% fewer cases in developing countries (<1.5 million cases/year) and 7.7% fewer cases in developed countries (<390
000 cases) (5
). In 2009, zur Hausen (6
) estimated that slightly >20% of the global cancer burden can be linked to infectious agents and predicted that this fraction will increase in the future.
provides an outline of the infections and infestations that have been associated so far with specific cancers in humans. A number of them have been categorized, according to the criteria of the International Agency for Research on Cancer (IARC), either in Group 1 (carcinogenic to humans), Group 2A (probably carcinogenic to humans), Group 2B (possibly carcinogenic to humans) or Group 3 (not classifiable as to carcinogenicity to humans). Of the microbial types and parasitic species evaluated so far by IARC (Volumes 1–100), 22 are categorized in Group 1, 1 in Group 2A and 16 in Group 2B. The last column in reports the estimates made by Parkin (5
) regarding the fraction of cancer attributable to specific infectious agents. It can be noted that the three major cancer-related infections are cumulatively associated with 15.6% of all human cancer cases in the world.
Viral and bacterial infections and trematode infestations associated with cancer in humans
The infections with HBV and HCV, which are the only hepatitis virus infections that tend to evolve chronically, are associated with occurrence of hepatocellular carcinoma (HCC). These two viruses are quite different from both taxonomic and structural standpoints. In fact, HBV is a DNA virus that belongs to the family of hepadnaviridae, together with other hepatotropic viruses that are pathogenic to animal species other than humans, among which the woodchuck hepatitis virus shares strict analogies with HBV also with respect to HCC pathogenesis. HCV is a positive-strand RNA virus related to the family of flaviviridae. Hepatitis D virus, also known as hepatitis delta antigen (HDAg), has a circular RNA genome and needs concurrent infection with a hepadnavirus for its replication. Although it has been shown that chronic hepatitis and cirrhosis develop more rapidly in case of HBV superinfection with Hepatitis D virus, there is no adequate demonstration of Hepatitis D virus contribution to HCC (7
). HBV and HCV infections were estimated to be associated with 4.9% of all cancer cases and specifically with 85.5% of all HCC cases in the world, 54.4% of which attributable to HBV and 31.1% attributable to HCV according to Parkin (5
). A similar figure (80.0%) was confirmed by zur Hausen (6
). Liver cancer is the third leading cause of cancer death in men and the sixth among women, with an expected number of 680
000 deaths in 2007 (23
Papillomaviruses and polyomaviruses are DNA viruses that formerly belonged to the family of papovaviridae, together with simian virus 40 (SV40) or vacuolizing virus. In fact, the papova prefix combines the two initial letters of papilloma, polioma and vacuolizing. The present taxonomy classifies papillomaviruses in the family of papillomaviridae, whereas both polyomaviruses and SV40 are in the family of polyomaviridae. HPV include >100 types, whose infection may become persistent and then progress to precancerous lesions and eventually to invasion by causing cancers in a variety of sites, including uterine cervix, vulva, vagina, penis, anus, oral cavity, oropharynx and possibly the skin in patients with epidermodysplasia verruciformis (8
). Recently, as summarized in , the IARC Working Group has reclassified the carcinogenicity of alpha, beta and gamma HPV types in Groups 1, 2A, 2B and 3 (9
). HPV infections were estimated to account for 5.2% of all cancers in the world, being responsible for 3% of mouth cancers, 12% of oropharynx cancers, 40% of penis cancers, 40% of vulva/vagina cancers and virtually 100% of uterine cervix cancers (5
). Cervical cancer is the second most commonly diagnosed cancer in women and is the third leading cause of cancer death in women worldwide. An estimated 309
800 deaths were expected to occur in 2007, >83% of which in developing countries (23
Among polyomaviruses, JC virus causes a fatal-demyelinating disease, the progressive multifocal leukoencephalopathy. JC virus is tumorigenic to several animal models and is suspected to be carcinogenic also to humans due to an increased incidence of central nervous system tumors (10
) and colorectal cancer (11
) in progressive multifocal leukoencephalopathy patients. The Merkel cell virus is the etiological agent of a skin cancer known as Merkel cell carcinoma (12
). SV40 is an extensively investigated oncogenic virus to rodents, which was a contaminant of live poliovirus vaccines that were administered to millions of children between 1955 and 1963. It has been suspected that SV40 may be associated with human malignant mesothelioma, due to the detection of viral DNA sequences in this cancer. However, this issue is controversial (13
Two DNA viruses belonging to the subfamily of gammaherpesviridae have been shown to be involved in the causation of human cancers. The Epstein–Barr virus or human herpesvirus (HHV) 4, belonging to the Lymphocryptovirus genus, is the etiological agent of infectious mononucleosis during adolescence and young adulthood. HHV4 is associated with multiple cancers and specifically with several types of lymphoma and with nasopharyngeal carcinoma (15
). The other herpesvirus, discovered in patients affected by acquired immune deficiency syndrome (AIDS), is denominated Kaposi's sarcoma-associated herpesvirus (KSHV) or HHV8, which is also related to primary effusion lymphoma (9
Besides HCV, other RNA viruses that have been associated with human cancers belong to the family of retroviridae. The virion of the HTLV contains two genomic RNA strands complexed with various enzymes, among which reverse transcriptase. HTLV-I has been associated with T-cell leukemia/lymphoma, whereas the evidence for HTLV-II carcinogenicity is so far inadequate (16
). The HIV-1, initially denominated HTLV-III or lymphoadenopathy-associated virus, and the structurally related HIV-2, classified in the group of lentiviruses, are the etiological agents of AIDS. Their virion has a single-stranded RNA genome within a protein core that contains reverse transcriptase. The severe immunodeficiency caused by HIV-1 has been associated with several human cancers and especially with Kaposi's sarcoma and non-Hodgkin's lymphoma, and a similar association is possibly involved also with HIV-2 (16
). Recently identified human endogenous retroviruses (HERV), and in particular human endogenous retrovirus-Q, play a potential role in the pathogenesis of human breast cancer (6
). The xenotropic murine leukemia virus-related virus, the first gammaretrovirus known to infect humans, has been associated with prostate cancer, especially high-grade tumors (17
Several bacteria are known or suspected to be related to cancers in humans (18
). The most important is H.pylori
, formerly named Campylobacter pyloridis
, a spiral or slightly curved gram-negative bacterium with two to six characteristic unipolar flagella, which is the main cause of chronic gastritis in humans and has been associated with both gastric cancer and gastric B-cell mucosa-associated lymphoid tissue lymphoma (MALT) (8
). Helicobacter pylori
was estimated to be associated with 5.5% of all cancers and specifically with 63.4 (5
) or 80.0% (6
) of stomach cancers. Note that stomach cancer, in 2007, was expected to remain the fourth most common malignancy in the world, with 1 million new cases, 70% of which in developing countries (23
Of other possible bacteria related to cancer, Streptococcus bovis
is a normal inhabitant of the human gastrointestinal tract that, according to several studies, may be involved in colorectal carcinogenesis (18
). Chronic infection of the gallbladder with Salmonella typhi
increases the risk of developing gallbladder carcinoma (18
). Arthropod-borne bartonellae cause persistent infection of erythrocytes and endothelial cells, whose massive proliferation can lead to vascular tumor formation in humans (20
). Besides exogenous bacteria, it has been suspected that indigenous microbes may play a role in cancer risk because they are part of our metabolism and makeup (21
). The human gut microbiome has been implicated in the etiology of localized intestinal diseases such as the irritable bowel syndrome, inflammatory bowel disease and colon cancer (24
). In addition, there is epidemiological evidence that the obligate intracellular Chlamydophila
may be associated with chronic lung diseases, also including lung cancer (18
In addition, infestations with trematode worms belonging to the phylum Platyhelminthes have been associated with human cancers. The association of Schistosoma haematobium
infestation with urinary bladder cancer is well established, whereas infestation with Schistosoma japonicum
is possibly associated with colorectal cancer and liver cancer (19
). Both Opistorchis viverrini
and Chlonorchis sinensis
infestations are convincingly demonstrated to be associated with occurrence of cholangiocarcinoma (8
Thus, on the whole, it appears that persistent infections are the leading causes for some of the most important human cancers, such as stomach cancer, cervical cancer and liver cancer. Collectively, their impact on human cancer epidemiology is just lower than that of the two dominating, lifestyle-related causes of cancer, i.e. tobacco smoking and dietary factors. Individually, the risk attributable to each one of the three major viral (HPV, HBV/HCV) and bacterial (H.pylori) chronic infections is higher than that attributable to important risk factors, such as environmental pollution.
It has been suggested that the burden of infection-related cancers is still underestimated worldwide due to the use of conservative population prevalence and risk ratio estimates (25
). In estimating the global burden of cancer, Thun et al.
) have predicted that, in the next 40 years, the demographic shift towards an increased longevity is compounded by the entrenchment of modifiable risk factors such as smoking and obesity in many low- and medium-resource countries and by the slower decline in cancers related to chronic infections in economically developing countries.