Infection: A Major Contributor to the Global Burden of Cancer

When most people think of the causes of cancer, factors such as environmental toxins or mutated genes spring to mind. Many would be surprised to learn that almost one in every five malignancies may stem from a less well-known source: infection.

In fact, data suggests that in 2002 nearly 18% of all cancers worldwide were attributable to infection, with infection-related malignancies being more common in the developing world than in the developed world in terms of both absolute numbers and the proportion of all cancers attributable to infection (26% vs. 7.7%)(1).

Major infective causes of cancers have in common the ability to become chronic and include:

1. hepatitis viruses (B and C), which are mainly responsible for hepatocellular carcinoma of the liver, but also for some non-Hodgkin lymphomas (hepatitis C),
2. the Helicobacter pylori bacterium, which is the main cause of cancers of the stomach and certain lymphomas of the stomach,
3. the human papillomavirus (HPV), which causes most cases of cancer of the anogenital tract, including almost all cases of cervical cancer, and some cases of cancer of the head and neck (including 20% of oropharyngeal cancers).

These estimates of the burden of infection related cancers are conservative for a number of reasons. Calculations of relative risks are hampered by inaccuracies in the estimated prevalence of infections in patients with cancer and in the population as whole. It is also not yet possible to distinguish between carcinogenic and less or non-carcinogenic strains of infection.

Other cancers may also be associated with infections for example, squamous cell carcinoma of the skin is probably related to HPV. Gallbladder cancer (which is common in some parts of the world) may be related to Helicobacter species or Salmonella typhi. A possible infective cause is also plausible for colon cancer, given the enormous exposure of the colon to intestinal flora, and childhood leukemia, given the geographical and temporal patterns observed.

Hepatocellular carcinoma of the liver
A recent meta-analysis of 90 studies of hepatocellular carcinoma, which included a total of 28,000 biopsies, detected the presence of antibodies to hepatitis C virus (HCV) in close to 40-50% of cases in some European countries, and slightly more than 20% even in countries with a relatively low risk of hepatitis, such as the United States. (2).

Surprisingly, although hepatitis B virus (HBV) predominates in countries such as China, Thailand and India, HCV accounts not only for the vast majority of cases of hepatocellular carcinoma in Japan (as expected) but is also more common than HBV in, for example, Mongolia and Pakistan. In addition, levels of HCV are high and increasing in Taiwan. The relative contribution of HCV to the current burden of liver cancer may thus be underestimated and prevention of HCV transmission should be strengthened.

Gastric cancer
Most epidemiological studies on H. pylori to date have been based on the detection of antibodies against the bacterium; however, this method is far from ideal.

The more carcinogenic and less carcinogenic strains are best differentiated by the presence or absence of the cagA gene, which is a marker of the cagA pathogenicity island (cag PAI). A cohort study of more than 2,100 high-risk individuals in Venezuela used the polymerase chain reaction (PCR) to distinguish cagA-negative strains of H. pylori from cagA-positive strains (3). H. pylori negative for cagA were associated with chronic gastritis as strongly as those positive for cagA, but were not associated with more severe lesions. The opposite is true for cagA-positive strains, which produce a risk of dysplasia (abnormal cells) that is 16 times higher than that in uninfected individuals. Failure to distinguish cagA-positive from cagA-negative strains of H. pylori can thus lead to the relative risk of gastric dysplasia being underestimated at 4.2 rather than 15.9.

Cervical cancer
The approval last year in the U.S. of the first cervical cancer vaccine targeting HPV focused new attention on the crucial role these pathogens play in spurring the disease.

In fact, a meta-analysis of close to 14,600 biopsies of invasive cervical cancer -- divided according to the continent in which they were collected &ndash showed that, worldwide, 70% of cervical cancers harbor the high-risk types of HPV-16 and -18 (which are covered in the current vaccines) (4).

Reassuringly, the proportion differs little across the different continents, although HPV-16 and -18 are slightly more frequent in Europe and North America (75%) than in Asia (67%) and Africa (70%) (Figure 1). Even more encouraging is the fact that the eight most frequent high-risk types of HPV are virtually the same worldwide, which is promising were a vaccine that covered all of these types ever to become available.

Given the importance of data on prevalence for sustaining spread of the prophylactic HPV vaccine worldwide, the International Agency for Research on Cancer (IARC) has been gathering information on the prevalence of the pathogen in different populations over the last 10 years (5, 6). Population-based samples, which have all been tested with a sensitive, validated PCR assay in the same laboratory, have been collected from 1,000 to 2,000 women. The results shows that worldwide variation in HPV prevalence is 10- to 20-fold, with a few countries, such as Spain and North Vietnam, having a very low prevalence but most nations having a prevalence of 10-15%. The highest HPV prevalence was found in Sub-Saharan Africa and Mongolia.

Other infectious organisms including the Epstein Barr virus (nasopharyngeal carcinoma and different types of lymphoma), Kaposi’s sarcoma-associated herpes virus (Kaposi’s Sarcoma), liver flukes (cholangiocarcinoma) and Schistosomiasis (bladder cancer) can also cause cancer. There is a significant unmet need to develop strategies to prevent these infection-related cancers, as well.

Clearly, a consensus is emerging that efforts to curb infection and infectious disease will also reduce the global burden of cancer. Those efforts, which include expanded immunization and other prevention programs, better treatment of infectious illness, and more research into the infection-cancer connection, have the potential to claim a dual victory for public health worldwide.

References

1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006 Jun 15;118(12):3030-44.
2. Raza SA, Clifford GM, Franceschi S. Worldwide variation in the relative importance of hepatitis B and hepatitis C viruses in hepatocellular carcinoma: a systematic review. Br J Cancer. 2007 Apr 10;96(7):1127-34.
3. Plummer M, van Doorn LJ, Franceschi S, Kleter B, Canzian F, Vivas J, et al. Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J Natl Cancer Inst. 2007 Sep 5;99(17):1328-34.
4. Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007;121:621-32.
5. Clifford GM, Gallus S, Herrero R, Munoz N, Snijders PJ, Vaccarella S, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet. 2005 Sep 17;366(9490):991-8.
6. Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, Anh PT, et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer. 2006 Dec 1;119(11):2677-84.