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The disparate origins of ovarian cancers: pathogenesis and prevention strategies

Nature Reviews Cancer volume 17, pages 65–74 (2017)Cite this article

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Abstract

Ovarian cancer is the fifth cause of cancer-related death in women and comprises a histologically and genetically broad range of tumours, including those of epithelial, sex cord-stromal and germ cell origin. Recent evidence indicates that high-grade serous ovarian carcinoma, clear cell carcinoma and endometrioid carcinoma primarily arise from tissues that are not normally present in the ovary. These histogenetic pathways are informing risk-reduction strategies for the prevention of ovarian and ovary-associated cancers and have highlighted the importance of the seemingly unique ovarian microenvironment.

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Figure 1: Anatomy and biology of the ovary, fallopian tube and uterus.
Figure 2: Adult granulosa cell tumour and Sertoli–Leydig cell tumour — a developmental perspective.
Figure 3: Pathogenesis of small cell carcinoma of the ovary, hypercalcaemic type.
Figure 4: Microenvironments of the ovary versus fallopian tube in tumour biology.

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References

  1. Young, R. H. From Krukenberg to today: the ever present problems posed by metastatic tumors in the ovary: part I. Historical perspective, general principles, mucinous tumors including the Krukenberg tumor. Adv. Anat. Pathol. 13, 205–227 (2006).

    Article  PubMed  Google Scholar 

  2. van der Linden, P. J. Theories on the pathogenesis of endometriosis. Hum. Reprod. 11 (Suppl. 3), 53–65 (1996).

    Article  PubMed  Google Scholar 

  3. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Cools, M., Wolffenbuttel, K. P., Drop, S. L., Oosterhuis, J. W. & Looijenga, L. H. Gonadal development and tumor formation at the crossroads of male and female sex determination. Sex. Dev. 5, 167–180 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Brennan, J. & Capel, B. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat. Rev. Genet. 5, 509–521 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Richards, J. S. & Pangas, S. A. The ovary: basic biology and clinical implications. J. Clin. Invest. 120, 963–972 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Al-Agha, O. M. et al. FOXL2 is a sensitive and specific marker for sex cord-stromal tumors of the ovary. Am. J. Surg. Pathol. 35, 484–494 (2011).

    Article  PubMed  Google Scholar 

  8. Costa, M. J., Ames, P. F., Walls, J. & Roth, L. M. Inhibin immunohistochemistry applied to ovarian neoplasms: a novel, effective, diagnostic tool. Hum. Pathol. 28, 1247–1254 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Movahedi-Lankarani, S. & Kurman, R. J. Calretinin, a more sensitive but less specific marker than α-inhibin for ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases. Am. J. Surg. Pathol. 26, 1477–1483 (2002).

    Article  PubMed  Google Scholar 

  10. Zhao, C. et al. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am. J. Surg. Pathol. 33, 354–366 (2009).

    Article  PubMed  Google Scholar 

  11. Fleming, N. I. et al. Aromatase is a direct target of FOXL2: C134W in granulosa cell tumors via a single highly conserved binding site in the ovarian specific promoter. PLoS ONE 5, e14389 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rosario, R., Araki, H., Print, C. G. & Shelling, A. N. The transcriptional targets of mutant FOXL2 in granulosa cell tumours. PLoS ONE 7, e46270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hes, O. et al. Mutational analysis (c.402C>G) of the FOXL2 gene and immunohistochemical expression of the FOXL2 protein in testicular adult type granulosa cell tumors and incompletely differentiated sex cord stromal tumors. Appl. Immunohistochem. Mol. Morphol. 19, 347–351 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Lima, J. F. et al. FOXL2 mutations in granulosa cell tumors occurring in males. Arch. Pathol. Lab. Med. 136, 825–828 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Lee, I. H. et al. Clinicopathologic characteristics of granulosa cell tumors of the ovary: a multicenter retrospective study. J. Gynecol. Oncol. 22, 188–195 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jamieson, S. et al. The FOXL2 C134W mutation is characteristic of adult granulosa cell tumors of the ovary. Mod. Pathol. 23, 1477–1485 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Schrader, K. A. et al. The specificity of the FOXL2 c.402C>G somatic mutation: a survey of solid tumors. PLoS ONE 4, e7988 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shah, S. P. et al. Mutation of FOXL2 in granulosa- cell tumors of the ovary. N. Engl. J. Med. 360, 2719–2729 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Boyd, N., Dancey, J. E., Gilks, C. B. & Huntsman, D. G. Rare cancers: a sea of opportunity. Lancet Oncol. 17, e52–e61 (2016).

    Article  PubMed  Google Scholar 

  20. Bellessort, B. et al. Role of Foxl2 in uterine maturation and function. Hum. Mol. Genet. 24, 3092–3103 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Benayoun, B. A. et al. Functional exploration of the adult ovarian granulosa cell tumor-associated somatic FOXL2 mutation p.Cys134Trp (c.402C>G). PLoS ONE 5, e8789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, J. H. et al. Differential apoptotic activities of wild-type FOXL2 and the adult-type granulosa cell tumor-associated mutant FOXL2 (C134W). Oncogene 30, 1653–1663 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Edson, M. A. et al. Granulosa cell-expressed BMPR1A and BMPR1B have unique functions in regulating fertility but act redundantly to suppress ovarian tumor development. Mol. Endocrinol. 24, 1251–1266 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pangas, S. A. et al. Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice. Mol. Cell. Biol. 28, 248–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Myers, M., Mansouri-Attia, N., James, R., Peng, J. & Pangas, S. A. GDF9 modulates the reproductive and tumor phenotype of female Inha-null mice. Biol. Reprod. 88, 86 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schmidt, D. et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131, 933–942 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Crisponi, L. et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat. Genet. 27, 159–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Uda, M. et al. Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum. Mol. Genet. 13, 1171–1181 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Uhlenhaut, N. H. et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139, 1130–1142 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Kalfa, N. et al. Aberrant expression of ovary determining gene FOXL2 in the testis and juvenile granulosa cell tumor in children. J. Urol. 180, 1810–1813 (2008).

    Article  PubMed  Google Scholar 

  31. Heravi-Moussavi, A. et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N. Engl. J. Med. 366, 234–242 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Anglesio, M. S. et al. Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage. J. Pathol. 229, 400–409 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, Y. et al. The oncogenic roles of DICER1 RNase IIIb domain mutations in ovarian Sertoli-Leydig cell tumors. Neoplasia 17, 650–660 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Barrionuevo, F. et al. Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol. Reprod. 74, 195–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Conlon, N. et al. A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors. Mod. Pathol. 28, 1603–1612 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Boer, C. M. et al. DICER1 RNase IIIb domain mutations are infrequent in testicular germ cell tumours. BMC Res. Notes 5, 569 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dickersin, G. R., Kline, I. W. & Scully, R. E. Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer 49, 188–197 (1982).

    Article  CAS  PubMed  Google Scholar 

  38. Young, R. H., Oliva, E. & Scully, R. E. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am. J. Surg. Pathol. 18, 1102–1116 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Scully, R. E. Tumors of the Ovary and Maldeveloped Gonads (Armed Forces Institute of Pathology, 1979).

    Google Scholar 

  40. Jelinic, P. et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat. Genet. 46, 424–426 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kupryjan´czyk, J. et al. Ovarian small cell carcinoma of hypercalcemic type — evidence of germline origin and SMARCA4 gene inactivation. a pilot study. Pol. J. Pathol. 64, 238–246 (2013).

    Article  Google Scholar 

  42. Ramos, P. et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat. Genet. 46, 427–429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Witkowski, L. et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat. Genet. 46, 438–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Foulkes, W. D. et al. No small surprise — small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J. Pathol. 233, 209–214 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Agaimy, A., Thiel, F., Hartmann, A. & Fukunaga, M. SMARCA4-deficient undifferentiated carcinoma of the ovary (small cell carcinoma, hypercalcemic type): clinicopathologic and immunohistochemical study of 3 cases. Ann. Diagn. Pathol. 19, 283–287 (2015).

    Article  PubMed  Google Scholar 

  47. Jelinic, P. et al. Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type. Mod. Pathol. 29, 60–66 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Karnezis, A. N. et al. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J. Pathol. 238, 389–400 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73, 5508–5518 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Wilson, B. G. et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol. Cell. Biol. 34, 1136–1144 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Glaros, S. et al. The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26, 7058–7066 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Kahali, B. et al. The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors. Oncotarget 5, 3316–3332 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yamamichi, N. et al. The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential. Oncogene 24, 5471–5481 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Florell, S. R., Bruggers, C. S., Matlak, M., Young, R. H. & Lowichik, A. Ovarian small cell carcinoma of the hypercalcemic type in a 14 month old: the youngest reported case. Med. Pediatr. Oncol. 32, 304–307 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Berchuck, A., Witkowski, L., Hasselblatt, M. & Foulkes, W. D. Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type. Gynecol. Oncol. Rep. 12, 20–22 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Pageaux, J. F., Laugier, C., Pal, D. & Pacheco, H. Development of the oviduct in quail during sexual maturation in relation to plasma concentrations of oestradiol and progesterone. J. Endocrinol. 100, 167–173 (1984).

    Article  CAS  PubMed  Google Scholar 

  57. Steinhauer, N., Boos, A. & Gunzel-Apel, A. R. Morphological changes and proliferative activity in the oviductal epithelium during hormonally defined stages of the oestrous cycle in the bitch. Reprod. Domest. Anim. 39, 110–119 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Verhage, H. G., Abel, J. H. Jr, Tietz, W. J. Jr & Barrau, M. D. Development and maintenance of the oviductal epithelium during the estrous cycle in the bitch. Biol. Reprod. 9, 460–474 (1973).

    Article  CAS  PubMed  Google Scholar 

  59. West, N. B. & Brenner, R. M. Estrogen receptor levels in the oviducts and endometria of cynomolgus macaques during the menstrual cycle. Biol. Reprod. 29, 1303–1312 (1983).

    Article  CAS  PubMed  Google Scholar 

  60. Donnez, J., Casanas-Roux, F., Caprasse, J., Ferin, J. & Thomas, K. Cyclic changes in ciliation, cell height, and mitotic activity in human tubal epithelium during reproductive life. Fertil. Steril. 43, 554–559 (1985).

    Article  CAS  PubMed  Google Scholar 

  61. Pearce, C. L. et al. Population distribution of lifetime risk of ovarian cancer in the United States. Cancer Epidemiol. Biomarkers Prev. 24, 671–676 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  62. McAlpine, J. N. et al. Opportunistic salpingectomy: uptake, risks, and complications of a regional initiative for ovarian cancer prevention. Am. J. Obstet. Gynecol. 210, 471.e1–471.e11 (2014).

    Article  Google Scholar 

  63. Eskenazi, B. & Warner, M. L. Epidemiology of endometriosis. Obstet. Gynecol. Clin. North. Am. 24, 235–258 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Pearce, C. L. et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies. Lancet Oncol. 13, 385–394 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  65. King, C. M., Barbara, C., Prentice, A., Brenton, J. D. & Charnock-Jones, D. S. Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma. J. Pathol. 238, 185–196 (2016).

    Article  PubMed  Google Scholar 

  66. Anglesio, M. S. et al. Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden. J. Pathol. 236, 201–209 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Jones, A. et al. Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development. PLoS Med. 10, e1001551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Somigliana, E. et al. Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence. Gynecol. Oncol. 101, 331–341 (2006).

    Article  PubMed  Google Scholar 

  70. Moll, U. M., Chumas, J. C., Chalas, E. & Mann, W. J. Ovarian carcinoma arising in atypical endometriosis. Obstet. Gynecol. 75, 537–539 (1990).

    CAS  PubMed  Google Scholar 

  71. LaGrenade, A. & Silverberg, S. G. Ovarian tumors associated with atypical endometriosis. Hum. Pathol. 19, 1080–1084 (1988).

    Article  CAS  PubMed  Google Scholar 

  72. Ogawa, S. et al. Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study. Gynecol. Oncol. 77, 298–304 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Fukunaga, M., Nomura, K., Ishikawa, E. & Ushigome, S. Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 30, 249–255 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Prefumo, F., Todeschini, F., Fulcheri, E. & Venturini, P. L. Epithelial abnormalities in cystic ovarian endometriosis. Gynecol. Oncol. 84, 280–284 (2002).

    Article  PubMed  Google Scholar 

  75. Jiang, X., Morland, S. J., Hitchcock, A., Thomas, E. J. & Campbell, I. G. Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res. 58, 1707–1712 (1998).

    CAS  PubMed  Google Scholar 

  76. Prowse, A. H. et al. Molecular genetic evidence that endometriosis is a precursor of ovarian cancer. Int. J. Cancer 119, 556–562 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Sato, N. et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 60, 7052–7056 (2000).

    CAS  PubMed  Google Scholar 

  78. Anglesio, M. S. et al. Synchronous endometrial and ovarian carcinomas: evidence of clonality. J. Natl Cancer Inst. 108, djv428 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Sieh, W. et al. Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case–control studies. Int. J. Epidemiol. 42, 579–589 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Buell-Gutbrod, R., Cavallo, A., Lee, N., Montag, A. & Gwin, K. Heart and neural crest derivatives expressed transcript 2 (HAND2): a novel biomarker for the identification of atypical hyperplasia and Type I endometrial carcinoma. Int. J. Gynecol. Pathol. 34, 65–73 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Herington, J. L., Bruner-Tran, K. L., Lucas, J. A. & Osteen, K. G. Immune interactions in endometriosis. Expert Rev. Clin. Immunol. 7, 611–626 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sanchez, A. M. et al. The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum. Reprod. Update 20, 217–230 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Vercellini, P. et al. Post-operative endometriosis recurrence: a plea for prevention based on pathogenetic, epidemiological and clinical evidence. Reprod. Biomed. Online 21, 259–265 (2010).

    Article  PubMed  Google Scholar 

  85. Crum, C. P., McKeon, F. D. & Xian, W. BRCA, the oviduct, and the space and time continuum of pelvic serous carcinogenesis. Int. J. Gynecol. Cancer 22, S29–S34 (2012).

    Article  PubMed  Google Scholar 

  86. Dubeau, L. & Drapkin, R. Coming into focus: the nonovarian origins of ovarian cancer. Ann. Oncol. 24, viii28–viii35 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kurman, R. J. & Shih, l.-M. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer — shifting the paradigm. Hum. Pathol. 42, 918–931 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Fathalla, M. F. Incessant ovulation — a factor in ovarian neoplasia? Lancet 2, 163 (1971).

    Article  CAS  PubMed  Google Scholar 

  89. Laviolette, L. A. et al. 17β-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer. Endocrinology 151, 929–938 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Ong, A., Maines-Bandiera, S. L., Roskelley, C. D. & Auersperg, N. An ovarian adenocarcinoma line derived from SV40/E-cadherin-transfected normal human ovarian surface epithelium. Int. J. Cancer 85, 430–437 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Sherman-Baust, C. A. et al. A genetically engineered ovarian cancer mouse model based on fallopian tube transformation mimics human high-grade serous carcinoma development. J. Pathol. 233, 228–237 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Miyoshi, I. et al. Mouse transgenic for murine oviduct-specific glycoprotein promoter-driven simian virus 40 large T-antigen: tumor formation and its hormonal regulation. Mol. Reprod. Dev. 63, 168–176 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Pothuri, B. et al. Genetic analysis of the early natural history of epithelial ovarian carcinoma. PLoS ONE 5, e10358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Dubeau, L. The cell of origin of ovarian epithelial tumors and the ovarian surface epithelium dogma: does the emperor have no clothes? Gynecol. Oncol. 72, 437–442 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Colgan, T. J., Murphy, J., Cole, D. E., Narod, S. & Rosen, B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am. J. Surg. Pathol. 25, 1283–1289 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Leeper, K. et al. Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol. Oncol. 87, 52–56 (2002).

    Article  PubMed  Google Scholar 

  97. Paley, P. J. et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol. Oncol. 80, 176–180 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Zweemer, R. P. et al. Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. Gynecol. Oncol. 76, 45–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Piek, J. M. et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J. Pathol. 195, 451–456 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Cass, I. et al. BRCA-mutation-associated fallopian tube carcinoma: a distinct clinical phenotype? Obstet. Gynecol. 106, 1327–1334 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Medeiros, F. et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am. J. Surg. Pathol. 30, 230–236 (2006).

    Article  PubMed  Google Scholar 

  102. Mehra, K. et al. STICS, SCOUTs and p53 signatures; a new language for pelvic serous carcinogenesis. Front. Biosci. (Elite Ed.) 3, 625–634 (2011).

    Google Scholar 

  103. Tone, A. A. et al. The role of the fallopian tube in ovarian cancer. Clin. Adv. Hematol. Oncol. 10, 296–306 (2012).

    PubMed  Google Scholar 

  104. Singh, N., Gilks, C. B., Wilkinson, N. & McCluggage, W. G. Assessment of a new system for primary site assignment in high-grade serous carcinoma of the fallopian tube, ovary, and peritoneum. Histopathology 67, 331–337 (2015).

    Article  PubMed  Google Scholar 

  105. Gilks, C. B. et al. Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas. Am. J. Surg. Pathol. 39, 357–364 (2015).

    Article  PubMed  Google Scholar 

  106. Morrison, J. C., Blanco, L. Z. Jr, Vang, R. & Ronnett, B. M. Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series. Am. J. Surg. Pathol. 39, 442–453 (2015).

    Article  PubMed  Google Scholar 

  107. Roh, M. H., Kindelberger, D. & Crum, C. P. Serous tubal intraepithelial carcinoma and the dominant ovarian mass: clues to serous tumor origin? Am. J. Surg. Pathol. 33, 376–383 (2009).

    Article  PubMed  Google Scholar 

  108. Banet, N. & Kurman, R. J. Two types of ovarian cortical inclusion cysts: proposed origin and possible role in ovarian serous carcinogenesis. Int. J. Gynecol. Pathol. 34, 3–8 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Bowen, N. J. et al. Emerging roles for PAX8 in ovarian cancer and endosalpingeal development. Gynecol. Oncol. 104, 331–337 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Laury, A. R. et al. A comprehensive analysis of PAX8 expression in human epithelial tumors. Am. J. Surg. Pathol. 35, 816–826 (2011).

    Article  PubMed  Google Scholar 

  111. Ordonez, N. G. Value of PAX 8 immunostaining in tumor diagnosis: a review and update. Adv. Anat. Pathol. 19, 140–151 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Ozcan, A. et al. PAX 8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. Mod. Pathol. 24, 751–764 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Marquez, R. T. et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin. Cancer Res. 11, 6116–6126 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Levanon, K. et al. Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis. Oncogene 29, 1103–1113 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Lee, Y. et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J. Pathol. 211, 26–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Jarboe, E. et al. Serous carcinogenesis in the fallopian tube: a descriptive classification. Int. J. Gynecol. Pathol. 27, 1–9 (2008).

    Article  PubMed  Google Scholar 

  117. Yemelyanova, A. et al. Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis. Mod. Pathol. 24, 1248–1253 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Gross, A. L., Kurman, R. J., Vang, R., Shih, l.-M. & Visvanathan, K. Precursor lesions of high-grade serous ovarian carcinoma: morphological and molecular characteristics. J. Oncol. 2010, 126295 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kindelberger, D. W. et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am. J. Surg. Pathol. 31, 161–169 (2007).

    Article  PubMed  Google Scholar 

  120. Leonhardt, K., Einenkel, J., Sohr, S., Engeland, K. & Horn, L. C. p53 signature and serous tubal in-situ carcinoma in cases of primary tubal and peritoneal carcinomas and serous borderline tumors of the ovary. Int. J. Gynecol. Pathol. 30, 417–424 (2011).

    Article  PubMed  Google Scholar 

  121. Yamamoto, Y. et al. In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells. J. Pathol. 238, 519–530 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Perets, R. et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 24, 751–765 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Prentice, L., Stewart, A., Mohiuddin, S. & Johnson, N. P. What is endosalpingiosis? Fertil. Steril. 98, 942–947 (2012).

    Article  PubMed  Google Scholar 

  124. Auersperg, N. The stem-cell profile of ovarian surface epithelium is reproduced in the oviductal fimbriae, with increased stem-cell marker density in distal parts of the fimbriae. Int. J. Gynecol. Pathol. 32, 444–453 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Auersperg, N. The origin of ovarian carcinomas: a unifying hypothesis. Int. J. Gynecol. Pathol. 30, 12–21 (2011).

    Article  PubMed  Google Scholar 

  126. Ng, A. & Barker, N. Ovary and fimbrial stem cells: biology, niche and cancer origins. Nat. Rev. Mol. Cell Biol. 16, 625–638 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Ning, G. et al. The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium. J. Pathol. 234, 478–487 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Paik, D. Y. et al. Stem-like epithelial cells are concentrated in the distal end of the fallopian tube: a site for injury and serous cancer initiation. Stem Cells 30, 2487–2497 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Garrett, L. A., Vargas, S. O., Drapkin, R. & Laufer, M. R. Does the fimbria have an embryologic origin distinct from that of the rest of the fallopian tube? Fertil. Steril. 90, 2008.e5–2008.e8 (2008).

    Article  Google Scholar 

  130. Bahar-Shany, K. et al. Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma. Gynecol. Oncol. 132, 322–327 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Kuhn, E., Kurman, R. J. & Shih, I. M. Ovarian cancer is an imported disease: fact or fiction? Curr. Obstet. Gynecol. Rep. 1, 1–9 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Cheng, E. J. et al. Molecular genetic analysis of ovarian serous cystadenomas. Lab. Invest. 84, 778–784 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Ho, C. L., Kurman, R. J., Dehari, R. & Wang, T. L. & Shih, l.-M. Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res. 64, 6915–6918 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Scully, R. E. Pathology of ovarian cancer precursors. J. Cell. Biochem. Suppl. 23, 208–218 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Kwon, J. S. et al. Costs and benefits of opportunistic salpingectomy as an ovarian cancer prevention strategy. Obstet. Gynecol. 125, 338–345 (2015).

    Article  PubMed  Google Scholar 

  136. Morelli, M. et al. Prophylactic salpingectomy in premenopausal low-risk women for ovarian cancer: primum non nocere. Gynecol. Oncol. 129, 448–451 (2013).

    Article  PubMed  Google Scholar 

  137. Arts-de Jong, M. et al. Risk-reducing salpingectomy with delayed oophorectomy in BRCA1/2 mutation carriers: patients' and professionals' perspectives. Gynecol. Oncol. 136, 305–310 (2015).

    Article  PubMed  Google Scholar 

  138. Harmsen, M. G. et al. Early salpingectomy (TUbectomy) with delayed oophorectomy to improve quality of life as alternative for risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers (TUBA study): a prospective non-randomised multicentre study. BMC Cancer 15, 593 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kwon, J. S. et al. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet. Gynecol. 121, 14–24 (2013).

    Article  PubMed  Google Scholar 

  140. [No authors listed.] The reduction in risk of ovarian cancer associated with oral-contraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N. Engl. J. Med. 316, 650–655 (1987).

  141. Hankinson, S. E. et al. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet. Gynecol. 80, 708–714 (1992).

    CAS  PubMed  Google Scholar 

  142. Havrilesky, L. J. et al. Oral Contraceptive Use for the Primary Prevention of Ovarian Cancer (AHRQ Publication, 2013).

    Google Scholar 

  143. Pike, M. C. et al. Hormonal factors and the risk of invasive ovarian cancer: a population-based case–control study. Fertil. Steril. 82, 186–195 (2004).

    Article  PubMed  Google Scholar 

  144. Schildkraut, J. M., Calingaert, B., Marchbanks, P. A., Moorman, P. G. & Rodriguez, G. C. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J. Natl Cancer Inst. 94, 32–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371, 303–314 (2008).

  146. Antoniou, A. C. et al. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol. Biomarkers Prev. 18, 601–610 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Modan, B. et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N. Engl. J. Med. 345, 235–240 (2001).

    Article  CAS  PubMed  Google Scholar 

  148. Narod, S. A. et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N. Engl. J. Med. 339, 424–428 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Ng, A. et al. Lgr5 marks stem/progenitor cells in ovary and tubal epithelia. Nat. Cell Biol. 16, 745–757 (2014).

    Article  CAS  PubMed  Google Scholar 

  150. Lau, A. et al. Altered expression of inflammation-associated genes in oviductal cells following follicular fluid exposure: implications for ovarian carcinogenesis. Exp. Biol. Med. 239, 24–32 (2014).

    Article  CAS  Google Scholar 

  151. McDaniel, A. S. et al. Next-generation sequencing of tubal intraepithelial carcinomas. JAMA Oncol. 1, 1128–1132 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Rabban, J. T., Vohra, P. & Zaloudek, C. J. Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. Am. J. Surg. Pathol. 39, 35–51 (2015).

    Article  PubMed  Google Scholar 

  153. Reyes, C., Murali, R. & Park, K. J. Secondary involvement of the adnexa and uterine corpus by carcinomas of the uterine cervix: a detailed morphologic description. Int. J. Gynecol. Pathol. 34, 551–563 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Scully, R. E. & Richardson, G. S. Luteinization of the stroma of metastatic cancer involving the ovary and its endocrine significance. Cancer 14, 827–840 (1961).

    Article  CAS  PubMed  Google Scholar 

  155. Pfleiderer, A. Jr & Teufel, G. Incidence and histochemical investigation of enzymatically active cells in stroma of ovarian tumors. Am. J. Obstet. Gynecol. 102, 997–1003 (1968).

    Article  PubMed  Google Scholar 

  156. Jacobs, I. J. et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 387, 945–956 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ardighieri, L. et al. Characterization of the immune cell repertoire in the normal fallopian tube. Int. J. Gynecol. Pathol. 33, 581–591 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ottolenghi, C. et al. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum. Mol. Genet. 16, 2795–2804 (2007).

    Article  CAS  PubMed  Google Scholar 

  159. Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This Opinion article is dedicated to N. Auersperg who encouraged the world to think seriously about ovarian cancer origins and continues to challenge and inspire our research. The authors thank M. Anglesio, N. Boyd and F. Kommoss for reviewing the manuscript and C. Crum for very helpful editorial comments. D.G.H. and A.N.K. are supported by Canadian Cancer Society Research Institute (CCSRI) Impact Grant 701603, CCSRI Innovation Grant 703458 and National Institutes of Health (NIH) R01 CA195670. K.R.C. is supported by NIH R01 CA196619 (KRC). C.L.P. is supported by NIH R01 CA141154, R01 CA136891, P30 CA046592 and R21 CA178571.

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  1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, V5Z 1M9, British Columbia, Canada

    Anthony N. Karnezis, C. Blake Gilks & David G. Huntsman

  2. Department of Pathology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Kathleen R. Cho

  3. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Celeste Leigh Pearce

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Correspondence to David G. Huntsman.

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Karnezis, A., Cho, K., Gilks, C. et al. The disparate origins of ovarian cancers: pathogenesis and prevention strategies. Nat Rev Cancer 17, 65–74 (2017). https://doi.org/10.1038/nrc.2016.113

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