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Cancer Genetics: Risks and Mechanisms of Cancer in Women with Hereditary Predisposition to Epithelial Ovarian Cancer

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Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in the developed world. This is primarily due to the fact that it is found in an advanced stage the majority of the time and that there are no successful and agreed-upon screening modalities. The majority of cases are also sporadic in nature, but a smaller percentage of cases are due to a hereditary predisposition. Gene mutations in BRCA1/2 and those that are a part of Lynch syndrome will increase a woman’s chance of developing ovarian cancer. When this is known, the woman could opt for heightened screening, medication prevention, or prophylactic surgeries. The medication and surgical interventions will either temporarily (e.g., breastfeeding, oral contraceptives) or permanently (e.g., tubal ligation, bilateral salpingo-oophorectomy) prevent pregnancy. As important as it is to identify the families for proper risk assessment, to impart knowledge, and to offer genetic testing in order to make proactive choices, this knowledge must take into account her decisions regarding future childbearing. While oncofertility is usually associated with individuals currently being treated for cancer, women at increased risk for developing EOC based on a hereditary predisposition should similarly be considered for oncofertility counseling and potentially for novel fertility-sparing interventions.

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References

  1. Woodruff TK, Snyder KA, editors. Oncofertility. Chicago: Springer; 2007.

    Google Scholar 

  2. National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast and ovarian. Version 1.2018—October 3, 2017. 2017. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed 18 Apr 2018.

  3. Jolie Pitt A. Angelina Jolie Pitt: diary of a surgery. The New York Times [online]. 2015. p. 1. Available at: https://www.nytimes.com/2015/03/24/opinion/angelina-jolie-pitt-diary-of-a-surgery.html. Accessed 18 Apr 2018.

  4. Schorge JO, Modesitt SC, Coleman RL, et al. SGO White Paper on ovarian cancer: etiology, screening and surveillance. Gynecol Oncol. 2010;119(1):7–17.

    Article  Google Scholar 

  5. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108(44):18032–7.

    Article  CAS  Google Scholar 

  6. International Agency for Research on Cancer (World Health Organization). In GLOBOCAN 2012: estimated cancer incidence mortality and prevalence worldwide in 2012. 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed 19 Apr 2018.

  7. American Cancer Society. In cancer facts & figures, 2018. 2018. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed 20 Apr 2018.

  8. Nelson HD, Fu R, Goddard K, et al. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: systematic review to update the U.S. Preventive Services Task Force recommendation. (2014). Ann Intern Med. 2013;160(4):255–66.

    Google Scholar 

  9. Sopik V, Iqbal J, Rosen B, et al. Why have ovarian cancer mortality rates declined? Part I. Incidence. Gynecol Oncol. 2015;138:741–9.

    Article  Google Scholar 

  10. Berek JS, Crum C, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstet. 2015;131:S111–22.

    Article  Google Scholar 

  11. Fleming GF, Seidman J, Lengyel E. Epithelial ovarian cancer. In: Barakat RR, Markman M, Randall ME, editors. Principles and practice of gynecologic oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 757–847.

    Google Scholar 

  12. Hankinson SE, Colditz GA, Hunter DJ, et al. A prospective study of reproductive factors and risk of epithelial ovarian cancer. Cancer. 1995;76:284–90.

    Article  CAS  Google Scholar 

  13. Wentzensen N, Poole EM, Trabert B, et al. Ovarian cancer risk factors by histologic subtype: an analysis from the Ovarian Cancer Cohort Consortium. J Clin Oncol. 2016;34:2888–98.

    Article  CAS  Google Scholar 

  14. van Leeuwen FE, Klip H, Mooij TM, et al. Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort. Hum Reprod. 2011;26:3456–65.

    Article  Google Scholar 

  15. Olsen CM, Nagle CM, Whiteman DC, et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr Relat Cancer. 2013;20:251–62.

    Article  Google Scholar 

  16. Bristow R, Armstrong D, editors. Early diagnosis and treatment of cancer: ovarian. Cambridge, MA: Elsevier; 2009.

    Google Scholar 

  17. Auranen A, Pukkala E, Makinen J, et al. Cancer incidence in the first degree relatives of ovarian cancer patients. Br J Cancer. 1996;74:280–4.

    Article  CAS  Google Scholar 

  18. Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst. 2014. https://doi.org/10.1093/jnci/dju091.

  19. Moorman PG, Havrilesky LJ, Gierisch JM, et al. Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta- analysis. J Clin Oncol. 2013;31:4188–98.

    Article  CAS  Google Scholar 

  20. Shuster LT, Gostout BS, Grossardt BR, et al. Prophylactic oophorectomy in premenopausal women and long-term health. Menopause Int. 2008;14:111–6.

    Article  Google Scholar 

  21. Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study. Obstet Gynecol. 2009;113:1027–37.

    Article  Google Scholar 

  22. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 2001;1:157–62.

    Article  CAS  Google Scholar 

  23. Ramus SJ, Harrington PA, Pye C, et al. Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat. 2007;28:1207–15.

    Article  CAS  Google Scholar 

  24. Bewtra C, Watson P, Conway T, et al. Hereditary ovarian cancer: a clinicopathological study. Int J Gynecol Pathol. 1992;11:180–7.

    Article  CAS  Google Scholar 

  25. Rebbeck TR, Mitra N, Wan F, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015;313(13):1347–61.

    Article  CAS  Google Scholar 

  26. Ewald IP, Ribeiro PL, Palmero EI, et al. Genomic rearrangements in BRCA1 and BRCA2: a literature review. Genet Mol Biol. 2009;32:437–46.

    Article  CAS  Google Scholar 

  27. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295:1379–88.

    Article  CAS  Google Scholar 

  28. Senst N, Llacuachaqui M, Lubinski J, et al. Parental origin of mutation and the risk of breast cancer in a prospective study of women with a BRCA1 or BRCA2 mutation. Clin Genet. 2013;84(1):43–6.

    Article  CAS  Google Scholar 

  29. Whittemore AS, Balise RR, Pharoah PD, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer. 2004;91:1911–5.

    Article  CAS  Google Scholar 

  30. Lynch HT, Casey MJ, Snyder CL, et al. Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management. Mol Oncol. 2009;3:97–137.

    Article  CAS  Google Scholar 

  31. Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015;2015:341723. https://doi.org/10.1155/2015/341723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–6.

    Article  CAS  Google Scholar 

  33. Rosenthal E, Moyes K, Arnell C, et al. Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry. Breast Cancer Res Treat. 2015;149:223–7.

    Article  CAS  Google Scholar 

  34. Johannesdottir G, Gudmundsson J, Bergthorsson JT, et al. High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res. 1996;56(16):3663–5.

    CAS  PubMed  Google Scholar 

  35. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62:676–89.

    Article  CAS  Google Scholar 

  36. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117–30.

    Article  CAS  Google Scholar 

  37. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329–33.

    Article  Google Scholar 

  38. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995;56:265–71.

    Article  CAS  Google Scholar 

  39. Satagopan JM, Boyd J, Kauff ND, et al. Ovarian cancer risk in Ashkenazi Jewish carrier of BRCA1 and BRCA2 mutations. Clin Cancer Res. 2002;8:3776–81.

    CAS  PubMed  Google Scholar 

  40. Mavaddat N, Peock S, Frost D, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105:812–22.

    Article  CAS  Google Scholar 

  41. Boland CR, Lynch HT. The history of Lynch syndrome. Familial Cancer. 2013;12(2):145–57.

    Article  Google Scholar 

  42. Meyer LA, Broaddus RR, Lu KH. Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control. 2009;16:14–22.

    Article  Google Scholar 

  43. Barrow E, Hill J, Evans DG. Cancer risk in Lynch syndrome. Familial Cancer. 2013;12:229–40.

    Article  CAS  Google Scholar 

  44. Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations. Gastroenterology. 2008;135:419–28.

    Article  CAS  Google Scholar 

  45. Baglietto L, Lindor NM, Dowty DM, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193–201.

    Article  CAS  Google Scholar 

  46. Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10.

    Article  CAS  Google Scholar 

  47. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol. 2014;109:1159–79.

    Article  Google Scholar 

  48. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA. 2006;296:1479–87.

    Article  CAS  Google Scholar 

  49. Smith MJ, Urquhart JE, Harkness EF, et al. The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Hum Mutat. 2016;37:250–6.

    Article  CAS  Google Scholar 

  50. Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271–2.

    Article  CAS  Google Scholar 

  51. Berends MJ, Wu Y, Sijmons RH, et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. 2002;70:26–37.

    Article  CAS  Google Scholar 

  52. Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21:1174–9.

    Article  Google Scholar 

  53. Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014;16:101–16.

    Article  CAS  Google Scholar 

  54. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosome Cancer. 2009;48:737–44.

    Article  CAS  Google Scholar 

  55. Goel A, Nguyen TP, Leung HC, et al. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer. 2011;128:869–78.

    Article  CAS  Google Scholar 

  56. Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32:407–14.

    Article  CAS  Google Scholar 

  57. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–6.

    Article  CAS  Google Scholar 

  58. American College of Obstetricians and Gynecologists. Lynch syndrome. Practice bulletin no. 147. Obstet Gynecol. 2014;124:1042–54.

    Article  Google Scholar 

  59. Lee JH, Cragun D, Thompson Z, et al. Association between IHC and MSI testing to identify mismatch repair-deficient patients with ovarian cancer. Genet Test Mol Biomark. 2014;18(4):229–35.

    Article  CAS  Google Scholar 

  60. National Comprehensive Cancer Network. NCCN guidelines for detection, prevention, & risk reduction. 2018. https://www.nccn.org/professionals/physician_gls/default.aspx#detection. Accessed 2 May 2018.

  61. Cantor SB, Bell DW, Ganesan S, et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001;105:149–60.

    Article  CAS  Google Scholar 

  62. Ramus SJ, Song H, Dicks E, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015. https://doi.org/10.1093/jnci/djv214.

  63. Easton DF, Lesueur F, Decker B, et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016;53(5):298–309.

    Article  CAS  Google Scholar 

  64. Hamosh A. *602774: RAD51, S. CEREVISIAE, HOMOLOG OF, C; RAD51C. In OMIM. 2013. https://www.omim.org/entry/602774?search=rad51c&highlight=rad51c. Accessed 2 Apr 2018.

  65. Meindl A, Hellebrand H, Wiek C, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42:410–4.

    Article  CAS  Google Scholar 

  66. Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43:879–82.

    Article  CAS  Google Scholar 

  67. Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13:581–8.

    Article  CAS  Google Scholar 

  68. Song H, Dicks E, Ramus SJ, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015;33:2901–7.

    Article  CAS  Google Scholar 

  69. Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122(23):3673–81.

    Article  CAS  Google Scholar 

  70. Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70–87.

    Article  Google Scholar 

  71. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

    Article  Google Scholar 

  72. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101:80–7.

    Article  CAS  Google Scholar 

  73. Segev Y, Iqbal J, Lubinski J, et al. The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study. Hereditary Breast Cancer Study Group. Gynecol Oncol. 2013;130:127–31.

    Article  CAS  Google Scholar 

  74. Kuhn E, Kurman RJ, Shih IM. Ovarian cancer is an imported disease: fact or fiction? Curr Obstet Gynecol Rep. 2012;1:1–9.

    Article  Google Scholar 

  75. Kurman RJ. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Ann Oncol. 2013;24(10):x16–21.

    Article  Google Scholar 

  76. Daly MB, Dresher CW, Yates MS, et al. Salpingectomy as a means to reduce ovarian cancer risk. Cancer Prev Res (Phila). 2015;8(5):342–8.

    Article  Google Scholar 

  77. Labidi-Galy SI, Papp E, Hallberg D, et al. Nat Commun. 2017. https://doi.org/10.1038/s41467-017-00962-1.

  78. Falconer H, Yin L, Gronberg H, et al. Ovarian cancer risk after salpingectomy: a nationwide population-based study. J Natl Cancer Inst. 2015. https://doi.org/10.1093/jnci/dju410.

  79. American College of Obstetricians and Gynecologists. Salpingectomy for ovarian cancer prevention. Committee opinion no. 620. Obstet Gynecol. 2015;125:279–81.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Clinical Genetics, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Andrew F. Wagner, Lee P. Shulman & Jeffrey S. Dungan

Authors
  1. Andrew F. Wagner
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  2. Lee P. Shulman
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  3. Jeffrey S. Dungan
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Corresponding author

Correspondence to Andrew F. Wagner .

Editor information

Editors and Affiliations

  1. Department of Obstetrics and Gynecology, Northwestern University , Chicago, IL, USA

    Teresa K. Woodruff

  2. Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA

    Divya K. Shah

  3. Department of Obstetrics and Gynecology, University of Rochester, Rochester, NY, USA

    Wendy S. Vitek

Review Questions and Answers

Review Questions and Answers

  1. Q1.

    CA-125 levels and pelvic ultrasounds have been shown to successfully identify epithelial ovarian cancer in an early or precancerous stage. True or False?

  2. A1.

    False

  1. Q2.

    BRCA1/2 mutations:

    1. (a)

      Are only inherited through the maternal line

    2. (b)

      Are only inherited through the paternal line

    3. (c)

      Can be seen more frequently in certain ethnicities as a founder mutation

    4. (d)

      Guarantee that a carrier will develop epithelial ovarian cancer

    5. (e)

      Increase the risk for colon cancer in carriers

  1. A2.

    (c)

  1. Q3.

    Lynch syndrome gene mutations:

    1. (a)

      Are associated with familial adenomatous polyposis

    2. (b)

      Are responsible for more epithelial ovarian cancer cases than BRCA1/2 mutations

    3. (c)

      Do not increase the risk for urogenital cancer

    4. (d)

      Have an ethnic predilection

    5. (e)

      May cause more endometrial cancer than ovarian cancer

  1. A3.

    (e)

  2. Q4.

    60% of ovarian cancers originate in the fallopian tubes. True or false?

  3. A4.

    True

  4. Q5.

    The most important element of cancer risk assessment is taking an accurate family history. True or false?

  5. A5.

    True

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Wagner, A.F., Shulman, L.P., Dungan, J.S. (2019). Cancer Genetics: Risks and Mechanisms of Cancer in Women with Hereditary Predisposition to Epithelial Ovarian Cancer. In: Woodruff, T., Shah, D., Vitek, W. (eds) Textbook of Oncofertility Research and Practice. Springer, Cham. https://doi.org/10.1007/978-3-030-02868-8_3

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