Infection and Cancer Epidemiology 242 2009 Major InfectionAssociated

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) § 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)

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

H. pylori Infection and Stomach Cancer

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

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

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

H. pylori and gastric cancer - Prospective studies: metaanalysis of non-cardia cancer cases.

H. pylori and gastric cancer - Prospective studies: metaanalysis of cardia cancer cases.

H. pylori Infection and Stomach Cancer in Whites at MSKCC H. Pylori no yes case/control 69/54 67/15 Infection rates: 21. 7% in controls 49. 3% in cases OR 1. 00 3. 50 (1. 80 -6. 79)

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 § Vac. A expression and “pathogenicity island” increase inflammation and damage § Anitbodies to Cag. A, an island protein, can be detected in serum and used to indicate more inflammatory strains

HPV and Cervical Cancer

§ § § 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 (E 6 and E 7) § 5. 2% of ALL cancers attributed to HPV

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

Map of the HPV-16 genome

Mechanism of Carcinogenesis § HPV DNA integrates into host genome. § Often, E 2/E 1 gets disrupted during integration and no longer regulates E 6/E 7 proteins. § E 6/E 7 expression increases. § E 6 interacts with p 53 and promotes the degradation of p 53. § E 7 interacts with p. RB and releases E 2 F which promotes cell cycle progression. § E 7 interacts with p 21 and inhibits it so that it cannot inhibit cyclin dependent kinase.

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:

HPV Testing and Typing § Low-risk: HPV 6, 11, 40 s, 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

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

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.

Classification of Cervical Squamous Neoplasia Dysplasia Pap. S. CIN scale Bethesda Normal Infla. Atypia Koilocyt. Atypia Mild dysplasia Moderate dysp. Severe dysp. Ca. in situ Invasive ca. 1 2 a 2 b 3 3 3 4 5 Normal LG SIL HG SIL Invasive ca Normal Infla. atypia Koilocyto a. CIN 1 CIN 2 CIN 3 Invasive ca

HBV and Liver Cancer

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)

Prevalence of chronic infection by HBV (HBs. Ag) and HCV (anti-HCV)

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

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

Taixing City, PRC Population-Based Case-Control Study: The relationship between liver cirrhosis and liver cancer Liver cirrhosis Case N % Control N % No 149(86. 6) 355(99. 2) Yes 23 (13. 4) 3 (0. 8) Crude OR (95%CI) Adjusted OR (95% CI) 18. 3(5. 40~61. 8) 22. 1(6. 11~79. 9)

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.

Self-reported hepatitis virus infection type Hepatitis History No Case N % 108(60. 34) Control N % 354(90. 08) Crude OR (95%CI) Adjusted OR (95% CI) 1 1 2. 67(1. 27~5. 60) HAV 16(8. 94) 19(4. 84) 2. 77(1. 38~5. 57) HBV 55(30. 73) 19(4. 40) 11. 30(6. 22~20. 5) 14. 52(7. 38~28. 6) HDV 0 (0) 1(0. 26)

Relationship between HBV vaccine and liver cancer HBV vaccine No Case N % 157(96. 32) Control N % 293(86. 14) Crude OR (95%CI) Adjusted OR (95% CI) 1 0. 24(0. 10~0. 57) 0. 24(0. 10~0. 60) Yes 6(3. 68) 47(13. 9)

Effects of HBs. Ag and anti-HCV on HCC development Variables Case Control Crude Age & Sex Adjusted N (%) OR (95%CI) Fully Adjusted** HBs. Ag - 72 (35. 3) 312 (75. 4) 1 1 1 + 132 (64. 7) 102 (24. 6) 5. 61 (3. 90 -8. 07) 5. 21 (3. 60 -7. 53) 5. 68 (3. 80 -8. 51) HCV - 183 (91. 0) 403 (97. 1) 1 1 1 + 18 (9. 0) 12 (2. 9) 3. 30 (1. 56 -7. 00) 3. 66 (1. 70 -7. 89) 4. 19 (1. 72 -10. 22) **Model includes age, sex, BMI, education, alcohol consumption, tobacco smoking, HBs. Ag, imputed AFB 1 levels, anti-HCV

Most frequent HBV infection spectrum in cases and controls TYPE HBs. Ag HBs. Ab HBe. Ag HBe. Ab HBc. Ab Crude OR (95%CI) Adjusteda (95%CI) 2 - - - 1. 00 1 - + - - - 0. 24 (0. 09~0. 63)* 0. 23 (0. 09~0. 61)* 3 - + - - + 1. 00 (0. 49~2. 03) 1. 02 (0. 49~2. 11) 1 + + - + + 4. 74 (2. 48~9. 06)* 3. 91 (1. 99~7. 66)* 2 + + - - + 8. 9 (4. 00~19. 73)* 7. 68 (3. 23~18. 31)* 3 + + + - + 12. 50 (4. 78~32. 73)* 11. 55 (4. 18~31. 90)*

Interaction between HBs. Ag and anti-HCV Anti-HCV HBs. Ag Case Control N (%) Crude OR (95% CI) Adjusted OR (95%CI) 1 No Negative 63(31. 19) 304(73. 08) Yes Negative 6(2. 97) 10(2. 40) 2. 90(1. 02~8. 26) 2. 63(0. 88~7. 85) No Positive 120(59. 41) 100(24. 04) 5. 79(3. 96~8. 46) 5. 20(3. 49~7. 76) Yes Positive 13(6. 44) 2(0. 48) 31. 37(6. 91~ 42. 44) 23. 99(5. 09~ 13. 12)

Interaction between HBV and IFNA 17 HBs. Ag Case Control Crude Fully Adjusted** N (%) OR (95%CI) N (%) IFNA 17 II - 13 (6. 8) 66 (17. 3) 1 1 RI&RR - 50 (26. 3) 220 (57. 6) 1. 15 (0. 59 -2. 25) 1. 34 (0. 64 -2. 82) II + 20 (10. 5) 27 (7. 1) 3. 76 (1. 64 -8. 62) 3. 99 (1. 54 -10. 32) RI&RR + 107 (56. 3) 69 (18. 1) 7. 87 (4. 04 -15. 34) 9. 18 (4. 34 -19. 43) ORint (95%CI)= 1. 81 (0. 71 -4. 62) 1. 71 (0. 60 -4. 92) IFNA 17 - 1. 15 (0. 59 -2. 25) 1. 35 (0. 63 -2. 85) (RI&RR vs. II) + 2. 09 (1. 09 -4. 02) 2. 19 (1. 01 -4. 76) **Model includes age, sex, BMI, education, alcohol consumption, tobacco smoking, imputed AFB 1 levels, anti-HCV

EBV and Cancer

Epstein-Barr Virus § § § Enveloped DNA virus Infects >90% of the population worldwide Transmitted by salivary exchange Infects both epithelial and B cells Associated with Burkitt’s lymphoma, Nasopharyngeal cancer (NPC), and lymphomas in immunocompromised patients § Mechanism of carcinogenesis: latent membrane protein 1 (LMP 1) located in host cell membrane – Lymphocytes: Inhibits apoptosis – Epithelial cells: Activates expression of (1) epidermal growth factor receptor and (2) antiapoptotic factor A 20

Cancers attributable to EBV **82% of Burkitt Lymphoma, 46% of Hodgkin Lymphoma, and 98% of NPC are attributable to EBV Source: Parkin, 2006

HIV and Cancer

HIV and Cancer § HIV strongly linked with Kaposi Sarcoma and Non-Hodgkin lymphoma § KS: HIV’s immunosuppression allows human herpes virus 8 (HHV-8) to replicate uncontrolled and increase viral load § However the incidence of non-AIDS-defining cancers (NADCs like lung, anal, cervical cancer) is increasing among those HIVinfected due to potent antiretroviral therapies

Cancers attributable to HIV or Human Herpes Virus 8 (HHV-8) **All cases of KS and 12% of NHL are attributable to HIV or HHV-8 Source: Parkin, 2006

Schistosomiasis and Cancer

Schistosomiasis § Over 200 million infected worldwide § Infection occurs through contact with water containing cercariae § Eggs elicit a chronic inflammatory response § Different species associated with different cancers – Schistosoma haematobium and urinary bladder cancer (10, 600 bladder cancer cases [3%] attributable to S. haematobium in 2002) – S. japonicum and colorectal cancer

HTLV I and Leukemia/Lymphoma

Human T-cell Lymphotropic Virus Type I § RNA virus § Prevalent in 5 -15% of adults in southwestern Japan, the Caribbean islands, South America, Central Africa, and parts of the Pacific Islands § Transmitted by (1) breast feeding, (2) blood transfusion, and (3) sexual intercourse § Usually acquired in infancy § Immortalizes CD 4 -positive T cells § Possible mechanisms of oncogenesis: Tax protein – Activates transcription factors – Suppresses transcriptional inhibitors – Suppresses cell-cycle inhibitors § Associated with Adult T-cell Leukemia

Cancers attributable to infections worldwide, 2002 Source: Parkin, 2006

Why some and not others? More to consider § Strain variation of infectious agent (e. g. HPV) § Host genetic variation (susceptibility to chronic infection and response to infection) § Circumstances of infection (e. g. acquired during childhood or adulthood) § Environmental cofactors (other risk factors or immunosuppression)

Intervention Strategies § Vaccinations and preventions against infection § Dietary Antioxidants § Omega-3 fatty acids (anti-inflammatory agents) § Anti-inflammatory Drugs, nonsteroidal antiinflammatory drugs (NSAIDS) such as aspirin