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Infection and Cancer

Infection and Cancer. Epidemiology 242 2009. Major Infection-Associated Malignancies. In 2002, 17.8% of the global cancer burden (1.9 million cases) were infection-attributable Malignancy (infection) Stomach cancer ( Helicobactor pylori ) Cervical cancer (human papillomavirus)

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Infection and Cancer

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  1. Infection and Cancer Epidemiology 242 2009

  2. Major Infection-Associated Malignancies In 2002, 17.8% of the global cancer burden (1.9 million cases) were infection-attributable Malignancy (infection) • Stomach cancer (Helicobactor pylori) • Cervical cancer (human papillomavirus) • Liver cancer (hepatitis B and C viruses) • Burkitt’s lymphoma and nasopharyngeal cancer (Epstein-Barr virus) • Kaposi sarcoma and Non-Hodgkin lymphoma (HIV/HHV-8) • Bladder and colon cancer (schistosomiasis) • Adult T-cell leukemia/lymphoma (human T-cell lymphotropic virus type I)

  3. Mechanisms of Infection-Induced Malignancy Chronic Inflammation and Carcinogenesis • Chronic host-pathogen interaction Immunosuppression • Chronic inflammation Oxidative Stress DNA damage and mutations Cell injury Cell division • Infection inducing Cell proliferation Production of Oncogenic Proteins Genomic Instability from Viral Genomic Integration

  4. H. pylori Infection and Stomach Cancer

  5. Helicobacter pylori • Helicobacter pylori was the first bacterium to be officially recognized as a cancer-causing agent • Flagellated gram-negative, spiral-shaped rod bacterium • Chronically infects 50% of the worldwide population • In developing countries, infection is universal among adults and about half of children <10 years are infected • In developed countries, 40-50% of adults are infected and infection among children is unusual • Roughly 1% of those infected eventually develop stomach cancer • Infection is inversely correlated with socioeconomic status (from household crowding, less household sanitation and hygiene) • Nitrates and nitrites are substances commonly found in cured meats, some drinking water, and certain vegetables, that can be converted by H. pylori into compounds that have been found to cause stomach cancer in animals • 5.5% of ALL cancers attributed to H. pylori

  6. World prevalence of H. pylori infection in adults Source: Parkin, 2006

  7. Stomach cancers attributable to H. pylori infection (2002) Source: Parkin, 2006

  8. H. pylori and gastric cancer - Prospective studies: meta-analysis of non-cardia cancer cases.

  9. H. pylori and gastric cancer - Prospective studies: meta-analysis of cardia cancer cases.

  10. H. pylori Infection and Stomach Cancer in Whites at MSKCC H. Pylori case/control OR no 69/54 1.00 yes 67/15 3.50 (1.80-6.79) Infection rates: 21.7% in controls 49.3% in cases

  11. Biomarker in Epidemiology: Biomarkers of Biological Agents • Biological agents associated with chronic infection and subsequent development of cancer are measured using serological or nucleic acid markers • VacA expression and “pathogenicity island” increase inflammation and damage • Anitbodies to CagA, an island protein, can be detected in serum and used to indicate more inflammatory strains

  12. HPV and Cervical Cancer

  13. Human Papillomavirus • Nonenveloped DNA virus • More than 70 different types • Infects the squamous epithelium of the genital tract, skin, and upper respiratory tract • Most infections are transient • Infection of the genital tract highly prevalent worldwide • Higher prevalence in younger women than older (In US, 30-40% in young women visiting university health clinics vs. 17% in older women visiting HMO clinics) • High-risk HPV detected in 90-95% of cervical cancers • Mechanism of carcinogenesis: oncogenic proteins (E6 and E7) • 5.2% of ALL cancers attributed to HPV

  14. Cancers attributable to HPV infection (2002) Source: Parkin, 2006

  15. Map of the HPV-16 genome

  16. Mechanism of Carcinogenesis • HPV DNA integrates into host genome. • Often, E2/E1 gets disrupted during integration and no longer regulates E6/E7 proteins. • E6/E7 expression increases. • E6 interacts with p53 and promotes the degradation of p53. • E7 interacts with pRB and releases E2F which promotes cell cycle progression. • E7 interacts with p21 and inhibits it so that it cannot inhibit cyclin dependent kinase.

  17. HPV Testing and Typing • HPV infection is the main cause of cervical cancer. • Only 10-20% persistent infections are at risk of neoplasia. • About 70 subtypes, of which 25 are tropic for genital tract. Those are subdivided into three categories:

  18. HPV Testing and Typing • Low-risk: HPV 6, 11, 40s, strongly associated with LGSIL, rarely associated with HGSIL, never associated with cancer • Intermediate-risk: HPV 31, 33, 35, 51, 52, strongly associated with HGSIL • High-risk: HPV 16, 18, 45, 56, strongly associated with HGSIL and cancer

  19. Biomarker in Epidemiology: Biomarkers of Biological Agents • HPV DNA by PCR-based assays • HPV infection is often transient, especially in young women so that repeated sampling is required to assess persistent HPV infections

  20. HPV Testing and Typing • HPV can be tested and typed by dot blot hybridization, southern blot hybridization, Hybrid Capture and PCR • High sensitivity but relatively low specificity, particular among young women • HPV typing has great potential as a primary screening tool for cervical cancer.

  21. Classification of Cervical Squamous Neoplasia

  22. HBV and Liver Cancer

  23. Hepatitis B Virus • Enveloped DNA virus • 350 million people chronically infected worldwide • Prevalence of chronic infection in high-prevalence areas can be as high as 10-15% • About 80% of liver cancers worldwide are in HBV-infected individuals • Those chronically infected have a 40% lifetime risk of developing HCC • Major pathways by which HBV infection increases risk for liver cancer are: (1) chronic inflammation (necroinflammatory liver disease) (2) oncogenic proteins (X protein) (3) genomic instability from viral DNA integration • 3.1% of ALL cancers attributed to HBV (4.9% to HBV and HCV)

  24. Prevalence of chronic infection by HBV (HBsAg) and HCV (anti-HCV)

  25. Liver cancers attributable to HBV or HCV **85% of liver cancers attributable to HBV or HCV Source: Parkin, 2006

  26. Cancer in cirrhotic liver • Up to 90% of HCC have co-existing cirrhosis

  27. Taixing City, PRC Population-Based Case-Control Study: The relationship between liver cirrhosis and liver cancer

  28. Biomarker in Epidemiology: Biomarkers of Biological Agents HBV infection by serological assays. • There are serological markers that distinguish between past and persistent infections. HBV DNA detection in sera further refines the assessment of exposure.

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