Etiologic Mechanisms in Epithelial Ovarian Cancer

  • Harvey A. Risch
Conference paper

Abstract

Ovarian cancer (OC) is a moderately common neoplasm of older women that is both difficult to diagnose and treat. Almost 2% of women are affected over the lifetime. It is the fourth most frequent cause of cancer death among women, after lung, breast, and colorectal cancer. The established risk factors (low parity, non-use of oral-contraceptives, germline BRCA1/2 mutation) account for a portion of disease occurrence, but mechanisms by which these factors affect risk of developing OC are not fully understood. The purpose of this chapter is to consider evidence for and against the two main etiologic hypotheses, concerning incessant ovulation and excessive gonadotropins. We use the term "ovarian cancer" to denote the borderline (low malignant potential) and invasive tumors of the surface epithelium of the ovary that constitute the more than 90% of all nonbenign ovarian neoplasms of adult women. Germ-cell, stromal, and other primary tumors also occur but are not the main focus here. Some etiologic heterogeneity may also exist among the epithelial subtypes, this is discussed by the author in detail elsewhere (1).

Keywords

Obesity Adenoma Oncol Progesterone Androgen 

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References

  1. 1.
    Risch HA, Marrett LD, Jain M et al. (1996) Differences in risk factors for epithelial ovarian cancer by histologic type: results of a case-control study. Am J Epidemiol 144:363–372.PubMedGoogle Scholar
  2. 2.
    Fathalla MF (1971) Incessant ovulation -a factor in ovarian neoplasia? Lancet 2:163.PubMedCrossRefGoogle Scholar
  3. 3.
    Casagrande JT, Pike MC, Ross RK et al. (1979) "Incessant ovulation" and ovarian cancer. Lancet 2:170–173.PubMedCrossRefGoogle Scholar
  4. 4.
    Cramer DW, Welch WR (1983) Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 71:717–721.Google Scholar
  5. 5.
    Franceschi S, Parazzini F, Negri E et al. (1991) Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use. Int J Cancer 49:61–65.Google Scholar
  6. 6.
    Whittemore AS, Harris R, Itnyre J et al. (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol 136:1184–1203.Google Scholar
  7. 7.
    Wilson JE (1958) Adeno-carcinomata in hens kept in a constant environment. Poultry Sci 37:1253.Google Scholar
  8. 8.
    Godwin AK, Testa JR, Handel LM et al. (1992) Spontaneous transformation of rat ovarian surface epithelial cells: Association with cytogenetic changes and implications of repeated ovulation in the etiology of ovarian cancer. J Natl Cancer Inst 84:592–601.PubMedCrossRefGoogle Scholar
  9. 9.
    Mittal KR, Zeleniuch-Jacquotte A, Cooper JL et al. (1993) Contralateral ovary in unilateral ovarian carcinoma: A search for preneoplastic lesions. Int J Gynecol Pathol 12:59–63.PubMedCrossRefGoogle Scholar
  10. 10.
    Westhoff C, Murphy P, Heller D et al. (1993) Is ovarian cancer associated with an increased frequency of germinal inclusion cysts? Am J Epidemiol 138:90–93.PubMedGoogle Scholar
  11. 11.
    Cruickshank DJ (1990) Aetiological importance of ovulation in epithelial ovarian cancer: a population based study. Br Med J 301:524–525.CrossRefGoogle Scholar
  12. 12.
    Hartge P, Devesa S (1995) Ovarian cancer, ovulation and side of origin. Br J Cancer 71:642–643.PubMedCrossRefGoogle Scholar
  13. 13.
    Potashnik G, Insler V, Meizner I et al. (1987) Frequency, sequence, and side of ovulation in women menstruating normally. Br Med J 294:219.CrossRefGoogle Scholar
  14. 14.
    Balasch J, Penarrubia J, Marquez M et al. (1994) Ovulation side and ovarian cancer. Gynecol Endocrinol 8:51–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Montesano R, Hainaut P, Wild CP (1997) Hepatocellular carcinoma: from gene to public health. J Natl Cancer Inst 89:1844–1851.PubMedCrossRefGoogle Scholar
  16. 16.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767.PubMedCrossRefGoogle Scholar
  17. 17.
    Eltabbakh GH, Belinson JL, Kennedy AW et al. (1997) p53 overexpression is not an independent prognostic factor for patients with primary ovarian epithelial cancer. Cancer 80:892–898.PubMedCrossRefGoogle Scholar
  18. 18.
    Berchuck A, Kohler MF, Hopkins MP et al. (1994) Overexpression of p53 is not a feature of benign and early-stage borderline epithelial ovarian tumors. Gynecol Oncol 52:232–236.PubMedCrossRefGoogle Scholar
  19. 19.
    Eltabbakh GH, Belinson JL, Kennedy AW et al. (1997) p53 and HER-2/neu overexpression in ovarian borderline tumors. Gynecol Oncol 65:218–224.PubMedCrossRefGoogle Scholar
  20. 20.
    Mazars R, Pujol P, Maudelonde T et al. (1991) p53 mutations in ovarian cancer: a late event? Oncogene 6:1685–1690.PubMedGoogle Scholar
  21. 21.
    SoodAK, Skilling JS, Buller RE(1997) Ovarian cancer genomic instability correlates with p53 frameshift mutations. Cancer Res 57:1047–1049.PubMedGoogle Scholar
  22. 22.
    Schildkraut JM, Bastos E, Berchuck A (1997) Relationship between lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer. J Natl Cancer Inst 89:932–938.PubMedCrossRefGoogle Scholar
  23. 23.
    Risch HA (1997) Re: Relationship between lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer. J Natl Cancer Inst 89:1726–1727.PubMedCrossRefGoogle Scholar
  24. 24.
    Risch HA, Marrett LD, Howe GR (1994) Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 140:585–597.PubMedGoogle Scholar
  25. 25.
    Harlow SD, Ephross SA (1995) Epidemiology of menstruation and its relevance to women’s health. Epidemiol Rev 17:265–286.PubMedGoogle Scholar
  26. 26.
    Parazzini F, La Vecchia C, Negri E et al. (1989) Menstrual factors and the risk of epithelial ovarian cancer. J Clin Epidemiol 42:443–448.PubMedCrossRefGoogle Scholar
  27. 27.
    Salazar H, Godwin AK, Daly MB et al. (1996) Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies. J Natl Cancer Inst 88:1810–1820.PubMedCrossRefGoogle Scholar
  28. 28.
    Resta L, Russo S, Colucci GA et al. (1993) Morphologic precursors of ovarian epithelial tumors. Obstet Gynecol 82:181–186.PubMedGoogle Scholar
  29. 29.
    Godwin AK, Perez RP, Johnson SW et al. (1992) Growth regulation of ovarian cancer. Hematol Oncol Clin North Am 6:829–841.PubMedGoogle Scholar
  30. 30.
    Biskind MS, Biskind GR (1944) Development of tumors in the rat ovary after transplantation into the spleen. Proc Soc Exp Biol Med 55:176–179.Google Scholar
  31. 31.
    Cramer DW (1990) Epidemiologic aspects of early menopause and ovarian cancer. Ann N Y Acad Sci 592:363–375.PubMedCrossRefGoogle Scholar
  32. 32.
    Tokuoka S, Kawai K, Shimizu Y et al. (1987) Malignant and benign ovarian neoplasms among atomic bomb survivors, Hiroshima and Nagasaki, 1950–1980. J Natl Cancer Inst 79:47–57.PubMedGoogle Scholar
  33. 33.
    Carr BR (1993) The ovary. In: Carr BR, Blackwell RE (eds) Textbook of reproductive medicine. Appleton and Lange, Norwalk, CT, pp. 183–207.Google Scholar
  34. 34.
    Rajaniemi H, Kauppila A, Ronnberg L et al. (1981) LH(hCG) receptor in benign and malignant tumors of human ovary. Acta Obstet Gynecol Scand Suppl 101:83–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Osterholzer HO, Streibel EJ, Nicosia S V (1985) Growth effects of protein hormones on cultured rabbit ovarian surface epithelial cells. Biol Reprod 33:247–258.PubMedCrossRefGoogle Scholar
  36. 36.
    Yong EL, Baird DT, Yates R et al. (1992) Hormonal regulation of the growth and steroidogenic function of human granulosa cells. J Clin Endocrinol Metab 74:842–849.PubMedCrossRefGoogle Scholar
  37. 37.
    Erickson GF, Garzo VG, Magoffin DA (1989) Insulin-like growth factor-I regulates aromatase activity in human granulosa and granulosa luteal cells. J Clin Endocrinol Metab 69:716–724.PubMedCrossRefGoogle Scholar
  38. 38.
    Henry RR (1996) Glucose control and insulin resistance in non-insulin-dependent diabetes mellitus. Ann Intern Med 124:97–103.PubMedGoogle Scholar
  39. 39.
    La Vecchia C, Negri E, Franceschi S et al. (1994) A case-control study of diabetes mellitus and cancer risk. Br J Cancer 70:950–953.PubMedCrossRefGoogle Scholar
  40. 40.
    Helzlsouer KJ, Alberg AJ, Gordon GB et al. (1995) Serum gonadotropins and steroid hormones and the development of ovarian cancer. J Am Med Ass 274:1926–1930.CrossRefGoogle Scholar
  41. 41.
    Guraya SS (1980) Histochemistry of the ovary. In: Motta PM, Hafez ESE (eds) Biology of the ovary. Martinus Nijhoff Publishers, New York, pp. 33–51.Google Scholar
  42. 42.
    Clement PB (1987) Histology of the ovary. Am J Surgical Pathol 11:277–303.CrossRefGoogle Scholar
  43. 43.
    Risch HA (1996) Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 63:254–257.PubMedCrossRefGoogle Scholar
  44. 44.
    Hoover R, Gray LA Sr, Fraumeni JF Jr (1977) Stilboestrol (diethylstilbestrol) and the risk of ovarian cancer. Lancet 2:533–534.PubMedCrossRefGoogle Scholar
  45. 45.
    Toppila M, Tyler JPP, Fay R et al. (1986) Steroid receptors in human ovarian malignancy: a review of four years tissue collection. Br J Obstet Gynaecol 93:986–992.PubMedCrossRefGoogle Scholar
  46. 46.
    Zeimet AG, Müller-Holzner E, Marth C et al. (1994) Immunocytochemical versus biochemical receptor determination in normal and tumorous tissues of the female reproductive tract and the breast. J Steroid Biochem Molec Biol 49:365–372.PubMedCrossRefGoogle Scholar
  47. 47.
    Ryder TA, Mobberley MA, Whitehead MI (1995) The endometrial nucleolar channel system as an indicator of progestin potency in HRT. Maturitas 22:31–36.PubMedCrossRefGoogle Scholar
  48. 48.
    Brenner PF, Mishell DR Jr, Stanczyk FZ et al. (1977) Serum levels of d-norgestrel, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone in women during and following ingestion of combination oral contraceptives containing dl-norgestrel. Am J Obstet Gynecol 129:133–140.PubMedGoogle Scholar
  49. 49.
    King RJB (1991) Biology of female sex hormone action in relation to contraceptive agents and neoplasia. Contraception 43:527–542.PubMedCrossRefGoogle Scholar
  50. 50.
    Rosenberg L, Palmer JR, Zauber AG et al. (1994) A case-control study of oral contraceptive use and invasive epithelial ovarian cancer. Am J Epidemiol 139:654–661.PubMedGoogle Scholar
  51. 51.
    Stubblefield PG (1993) Contraception. In: Copeland LJ, Jarrell JF, McGregor JA (eds) Textbook of gynecology. WB Saunders Co., Philadelphia, pp. 156–188.Google Scholar
  52. 52.
    Mishell DR Jr (1996) Pharmacodynamics of depot medroxyprogesterone acetate contraception. J Reprod Med 41:381–390.PubMedGoogle Scholar
  53. 53.
    Stanford JL, Thomas DB (1991) Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 49:191–195.Google Scholar
  54. 54.
    Mink PJ, Folsom AR, Sellers TA et al. (1996) Physical activity, waist-to-hip ratio, and other risk factors for ovarian cancer: a follow-up study of older women. Epidemiology 7:38–45.PubMedCrossRefGoogle Scholar
  55. 55.
    Ellison PT, Lager C (1986) Moderate recreational running is associated with lowered salivary progesterone profiles in women. Am J Obstet Gynecol 154:1000–1003.PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 2001

Authors and Affiliations

  • Harvey A. Risch

There are no affiliations available

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