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REPRODUCTIVE PATHOPHYS III Cancers of the Reproductive System

REPRODUCTIVE PATHOPHYS III Cancers of the Reproductive System. Julie Kasperzyk , Sc.D. November 12, 2012. Acquired capabilities of cancer. From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674. Additional characteristics of some cancers.

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REPRODUCTIVE PATHOPHYS III Cancers of the Reproductive System

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  1. REPRODUCTIVE PATHOPHYS IIICancers of the Reproductive System Julie Kasperzyk, Sc.D. November 12, 2012

  2. Acquired capabilities of cancer From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674

  3. Additional characteristics of some cancers From: Hanahan D. Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674

  4. Tumor development occurs in stages (1) Weinberg RA. How cancer arises. Sci Am. 1996 Sep;275(3):62-70.

  5. Tumor development occurs in stages (2) Weinberg RA. How cancer arises. Sci Am. 1996 Sep;275(3):62-70.

  6. Malignant versus Benign Tumors Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time http://www.cancer.gov/cancertopics/understandingcancer/cancer

  7. DNA Mutation C A A G C T A A C T DNA Normal gene C A A G C G A A C T Single base change C A A G G C G C T A A C T Additions C T C A A G A A C T Deletions http://www.cancer.gov/cancertopics/understandingcancer/cancer

  8. General genetic abnormalities in cancer cells (1) • Oncogenes get activated or become expressed more than normal • Oncogene: a gene that, when mutated or dysregulated, participates in the onset and development of cancer • The protein may be • expressed at a greater level (more protein in the cell) • become more active • lose its potential to be regulated • increase its stability (hang around in the cell longer) • These changes can cause the cell to be hyper-responsive to growth signals, grow in the absence of proper growth signals, evade apoptosis, etc.

  9. A) Oncogene example: HER2+ breast cancer

  10. General genetic abnormalities in cancer cells (2) • Tumor suppressor genes stop working • Tumor suppressor gene: a gene that protects a cell from one step in the cancer pathogenesis process • The gene product may be a protein that maintains the normal cell cycle, inhibits an oncogene, inhibits cell division, etc. • When a tumor suppressor gene is mutated or dysregulated, the cell can progress to cancer if other aberrations are also present

  11. B) Tumor suppressor example: p53 loss p53 protein Normal cell Excessive DNA damage Cell suicide (Apoptosis) • In normal cells, p53 protein triggers apoptosis http://www.cancer.gov/cancertopics/understandingcancer/cancer

  12. Environmental carcinogens • Viruses • DNA (ex: HPV) • RNA retroviruses (ex: HIV) • Chemical carcinogens • Can cause chemical changes in DNA, DNA breaks, and/or inflammation • Ex: asbestos, benzene, diesel exhaust • UV and ionizing radiation • Causes chromosomal breaks and translocations, and can interfere with DNA repair

  13. Cancer can spread to other sites (1) Ruoslahti E. How cancer spreads. Sci Am. 1996 Sep;275(3):72-7.

  14. Cancer can spread to other sites (2) Ruoslahti E. How cancer spreads. Sci Am. 1996 Sep;275(3):72-7.

  15. New cases of cancer in the US American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society.

  16. Cancer deaths among US men

  17. Cancer deaths among US women (includes cervix)

  18. male cancers

  19. Testicular cancer • Very rare: 8,590 new cases and 360 deaths annually in US • Most common form of cancer in men 16-34 • Median age at diagnosis is 33 • Most (90%) of cases arise from germ cells in the testes

  20. Testicular cancer risk factors • Northern European residence • Family history • Race/ethnicity: rates are 6x higher in Caucasians than African americans • Testicular dysgenesis syndrome • Carcinoma in situ can sometimes progress to invasive cancer • HIV infection (debatable) • Body size: taller and leaner men show highest risk

  21. Height (per 5cm) & testicular cancer risk British Journal of Cancer (2010) 103, 1467 – 1474

  22. BMI (per kg/m2) & testicular cancer risk British Journal of Cancer (2010) 103, 1467 – 1474

  23. Family history & prostate cancer risk Bratt et al. J Urol 2002;168:906-13

  24. Genetics & prostate cancer: 8q24 • Multiple genetic variants in this region found to increase PCa risk in variety of racial/ethnic groups • Not in a coding region • Closest gene is MYC, a transcription factor and oncogene • Not clear how/if risk variants in 8q24 regulate MYC function or expression Amundadottir et al. Nat Genet. 2006 Jun;38(6):652-8. Freedman et al. Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14068-73.

  25. 8q24 “Gene Desert” Region and Associations with Various Cancers PROSTATE COLORECTAL OVARIAN PROSTATE BREAST PROSTATE J Natl Cancer Inst 2008;100: 962 – 966

  26. Prostate cancer incidence & mortality rates by race World J Urol (2012) 30:195–200

  27. Diet & prostate cancer risk Giovannucci et al. Int. J. Cancer: 121, 1571–1578 (2007) Wilson et al. J Natl Cancer Inst. 2011;103(11):876-84. Chan et al. J ClinOncol 23:8152-8160

  28. Other risk factors for prostate cancer

  29. Height & BMI: potential mechanisms • Height • Proxy for nutritional status in early life • Growth factors and hormones • Obesity • Increased total energy intake • Metabolic syndrome & poor insulin control  increased cell proliferation

  30. Role of energy balance in cancer development Exp Diabetes Res. 2012;2012:789174

  31. Infection & prostate cancer: T. vaginalis • Parasitic protozoan • Infection affects 5-20% of U.S. young adults, typically asymptomatic in males • Causes inflammation and may induce anti-apoptosis genes • Preliminary data suggest that infection is linked to higher risk of aggressive prostate cancer

  32. Female cancers

  33. http://seer.cancer.gov/faststats/index.php

  34. American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

  35. American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

  36. Breast cancer risk factors: high estrogen exposure • Reproductive factors that increase level or duration of exposure to estrogen increase risk • Nulliparity • Early menarche • Late menopause • Postmenopausal hormone use • Older forms of birth control pills (high estrogen) • Postmenopausal obesity (fat cells produce estrogen) • Alcohol use (increases conversion of testosterone to estrogen)

  37. Risk factors for postmenopausal breast cancer across the life course Breast Disease 24 (2005,2006) 17–35

  38. Race/Ethnicity and Breast Cancer American Cancer Society. BreastCancer Facts & Figures 2011-2012. Atlanta: American Cancer Society.

  39. Heredity and Breast Cancer All Breast Cancer Patients Inherited factor(s) Other factor(s) http://www.cancer.gov/cancertopics/understandingcancer/cancer

  40. BRCA1 & BRCA2 mutations • Tumor suppressor genes • Normally, BRCA1 and BRCA2 help to stabilize DNA and prevent uncontrolled cellular proliferation • Prevalence of BRCA1 mutations in the general population is estimated between 1/500 to 1/1000 • Prevalence of BRCA2 mutations is lower, but not known precisely

  41. BRCA mechanism Hum Mol Genet. 2001;10:705-13

  42. BRCA1 & breast-ovarian cancer risk Am.J. Hum. Genet. 52:678-701, 1993

  43. http://seer.cancer.gov/faststats/index.php

  44. American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

  45. American Cancer Society. Global Cancer Facts & Figures 2nd Edition. Atlanta: American Cancer Society; 2011.

  46. Cervical cancer risk factors • Virtually all cervical cancers are caused by HPV infections • Other risk factors: • Sexual behavior: 1st intercourse at early age; multiple partners • Family history • Poor diet and overweight • HIV infection (weakens immune system) • Oral contraceptives • Multiple pregnancies May reflect sexual behaviors

  47. HPV infection • DNA virus • Viral proteins (E6 & E7) disrupt tumor suppressor genes in infected cells • 100+ subtypes, but only some (mainly HPV-16 and HPV-18) can cause cervical cancer • Most infections cleared by the immune system without any clinical symptoms Gynecologic Oncology Volume 107, Issue 2, Supplement 2007 S2 - S5

  48. Prevalence of HPV-16 in serum Infect Dis Obstet Gynecol. 2006;2006 Suppl:40470.

  49. Cumulative incidence of CIN after HPV infection Cervical Intraepithelial Neoplasia (CIN): precancerous lesion Infect Dis Obstet Gynecol. 2006;2006 Suppl:40470.

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