Skip to main content

Advertisement

SpringerLink
Log in

An allelotype analysis indicating the presence of two distinct ovarian clear-cell carcinogenic pathways: endometriosis-associated pathway vs. clear-cell adenofibroma-associated pathway

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Patterns of allele loss (loss of heterozygosity (LOH)) were studied to identify the genetic backgrounds underlying the two putative carcinogenic pathways of ovarian clear-cell adenocarcinoma: carcinomas thought to arise in endometriosis (endometriosis-associated carcinomas, 20 cases) and carcinomas thought to be derived from clear-cell adenofibroma ((CCAF)-associated carcinomas, 14 cases). Each tumor was assessed for LOH at 24 polymorphic loci located on 12 chromosomal arms: 1p, 3p, 5q, 8p, 9p, 10q, 11q, 13q, 17p, 17q, 19p, and 22q. For all informative loci, the frequency of LOH was not statistically different between the two carcinoma groups: 38% (66/172 loci) in the endometriosis-associated carcinomas and 35% (40/113 loci) in the CCAF-associated carcinomas. In the endometriosis-associated carcinomas, LOH was detected at high frequencies (>50%) at 3p, 5q, and 11q and at low frequencies (<20%) at 8p, 13q, and 17p. In the CCAF-associated carcinomas, LOH was detected at high frequencies at 1p, 10q, and 13q and at low frequencies at 3p, 9p, 11q, and 17q. The frequencies of LOH at chromosomes 3p, 5q, and 11q were significantly higher in the endometriosis-associated carcinomas than in the CCAF-associated carcinomas (P = 0.026, 0.007, and 0.011, respectively). Immunohistochemical analysis demonstrated a close association between the allelic status of the 3p25–26 locus and levels of von Hippel–Lindau (VHL) protein expression (P = 0.0026). These data further support the presence of two distinct carcinogenic pathways to ovarian clear-cell adenocarcinoma; the allelic status of the 3p, 5q, and 11q loci may provide a means to identify the precursor lesions of these carcinomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Seidman JD, Russell P, Kurman RJ (2001) Surface epithelial tumors of the ovary. In: Kurman RJ (ed) Blaustein's pathology of the female genital tract, 5th edn. Springer, New York, pp 791–904

    Google Scholar 

  2. Sugiyama T, Kamura T, Kigawa J et al (2000) Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 88:2584–2589

    Article  PubMed  CAS  Google Scholar 

  3. Ikeda K, Sakai K, Yamamoto R et al (2003) Multivariate analysis for prognostic significance of histologic subtype, GST-pi, MDR-1, and p53 in stages II–IV ovarian cancer. Int J Gynecol Cancer 13:776–784

    Article  PubMed  CAS  Google Scholar 

  4. Tavassoli FA, Devilee P (eds) (2003) World Health Organization classification of tumours. Pathology and genetics of tumours of the breast and female genital organs. IARC Press, Lyon

    Google Scholar 

  5. Kaku T, Ogawa S, Kawano Y et al (2003) Histological classification of ovarian cancer. Med Electron Microsc 36:9–17

    Article  PubMed  Google Scholar 

  6. Gynecologic Cancer Comittee, Japan Society of Obstetrics and Gynecology (2008) Annual report of gynecological cancer patients in Japan 2006. Acta Obstet Gynaecol Jpn 60:1001–1085 (in Japanese)

    Google Scholar 

  7. Sampson JA (1925) Endometrial carcinoma of the ovary arising in endometrial tissue in that organ. Arch Surg 10:1–72

    Google Scholar 

  8. Vercellini P, Parazzini F, Bolis G et al (1993) Endometriosis and ovarian cancer. Am J Obstet Gynecol 169:181–182

    PubMed  CAS  Google Scholar 

  9. Fukunaga M, Nomura K, Ishikawa E et al (1997) Ovarian atypical endometriosis: its close association with malignant epithelial tumours. Histopathology 30:249–255

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. LaGrenade A, Silverberg SG (1988) Ovarian tumors associated with atypical endometriosis. Hum Pathol 19:1080–1084

    Article  PubMed  CAS  Google Scholar 

  12. Mostoufizadeh M, Scully RE (1980) Malignant tumors arising in endometriosis. Clin Obstet Gynecol 23:951–963

    Article  PubMed  CAS  Google Scholar 

  13. Seidman JD (1996) Prognostic importance of hyperplasia and atypia in endometriosis. Int J Gynecol Pathol 15:1–9

    Article  PubMed  CAS  Google Scholar 

  14. Varma R, Rollason T, Gupta JK et al (2004) Endometriosis and the neoplastic process. Reproduction 127:293–304

    Article  PubMed  CAS  Google Scholar 

  15. Jiang X, Hitchcock A, Bryan EJ et al (1996) Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. Cancer Res 56:3534–3539

    PubMed  CAS  Google Scholar 

  16. Jiang X, Morland SJ, Hitchcock A et al (1998) Allelotyping of endometriosis with adjacent ovarian carcinoma reveals evidence of a common lineage. Cancer Res 58:1707–1712

    PubMed  CAS  Google Scholar 

  17. Sato N, Tsunoda H, Nishida M et al (2000) 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

    PubMed  CAS  Google Scholar 

  18. Bell DA, Scully RE (1985) Benign and borderline clear cell adenofibromas of the ovary. Cancer 56:2922–2931

    Article  PubMed  CAS  Google Scholar 

  19. Roth LM, Langley FA, Fox H et al (1984) Ovarian clear cell adenofibromatous tumors. Benign, of low malignant potential, and associated with invasive clear cell carcinoma. Cancer 53:1156–1163

    Article  PubMed  CAS  Google Scholar 

  20. Yamamoto S, Tsuda H, Yoshikawa T et al (2007) Clear cell adenocarcinoma associated with clear cell adenofibromatous components: a subgroup of ovarian clear cell adenocarcinoma with distinct clinicopathologic characteristics. Am J Surg Pathol 31:999–1006

    Article  PubMed  Google Scholar 

  21. Yamamoto S, Tsuda H, Takano M et al (2008) Clear-cell adenofibroma can be a clonal precursor for clear-cell adenocarcinoma of the ovary: a possible alternative ovarian clear-cell carcinogenic pathway. J Pathol 216:103–110

    PubMed  CAS  Google Scholar 

  22. Yamamoto S, Tsuda H, Takano M et al (2008) Expression of platelet-derived growth factors and their receptors in ovarian clear-cell carcinoma and its putative precursors. Mod Pathol 21:115–124

    PubMed  CAS  Google Scholar 

  23. Veras E, Mao TL, Ayse A et al (2009) Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Surg Pathol 33:844–853

    Article  PubMed  Google Scholar 

  24. Cliby W, Ritland S, Hartmann L et al (1993) Human epithelial ovarian cancer allelotype. Cancer Res 53:2393–2398

    PubMed  CAS  Google Scholar 

  25. Dodson MK, Hartmann LC, Cliby WA et al (1993) Comparison of loss of heterozygosity patterns in invasive low-grade and high-grade epithelial ovarian carcinomas. Cancer Res 53:4456–4460

    PubMed  CAS  Google Scholar 

  26. Sato T, Saito H, Morita R et al (1991) Allelotype of human ovarian cancer. Cancer Res 51:5118–5122

    PubMed  CAS  Google Scholar 

  27. Osborne RJ, Leech V (1994) Polymerase chain reaction allelotyping of human ovarian cancer. Br J Cancer 69:429–438

    PubMed  CAS  Google Scholar 

  28. Simsir A, Palacios D, Linehan WM et al (2001) Detection of loss of heterozygosity at chromosome 3p25–26 in primary and metastatic ovarian clear-cell carcinoma: utilization of microdissection and polymerase chain reaction in archival tissues. Diagn Cytopathol 24:328–332

    Article  PubMed  CAS  Google Scholar 

  29. Okada S, Tsuda H, Takarabe T et al (2002) Allelotype analysis of common epithelial ovarian cancers with special reference to comparison between clear cell adenocarcinoma with other histological types. Jpn J Cancer Res 93:798–806

    PubMed  CAS  Google Scholar 

  30. Dent J, Hall GD, Wilkinson N et al (2003) Cytogenetic alterations in ovarian clear cell carcinoma detected by comparative genomic hybridisation. Br J Cancer 88:1578–1583

    Article  PubMed  CAS  Google Scholar 

  31. Suehiro Y, Sakamoto M, Umayahara K et al (2000) Genetic aberrations detected by comparative genomic hybridization in ovarian clear cell adenocarcinomas. Oncology 59:50–56

    Article  PubMed  CAS  Google Scholar 

  32. Shuin T, Yamasaki I, Tamura K et al (2006) Von Hippel–Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol 36:337–343

    Article  PubMed  Google Scholar 

  33. Kinzler KW, Nilbert MC, Su LK et al (1991) Identification of FAP locus genes from chromosome 5q21. Science 253:661–665

    Article  PubMed  CAS  Google Scholar 

  34. Savitsky K, Bar-Shira A, Gilad S et al (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749–1753

    Article  PubMed  CAS  Google Scholar 

  35. Zheng JP, Robinson WR, Ehlen T et al (1991) Distinction of low grade from high grade human ovarian carcinomas on the basis of losses of heterozygosity on chromosomes 3, 6, and 11 and HER-2/neu gene amplification. Cancer Res 51:4045–4051

    PubMed  CAS  Google Scholar 

  36. Lounis H, Mes-Masson AM, Dion F et al (1998) Mapping of chromosome 3p deletions in human epithelial ovarian tumors. Oncogene 17:2359–2365

    Article  PubMed  CAS  Google Scholar 

  37. Allan GJ, Cottrell S, Trowsdale J et al (1994) Loss of heterozygosity on chromosome 5 in sporadic ovarian carcinoma is a late event and is not associated with mutations in APC at 5q21–22. Hum Mutat 3:283–291

    Article  PubMed  CAS  Google Scholar 

  38. Gabra H, Watson JE, Taylor KJ et al (1996) Definition and refinement of a region of loss of heterozygosity at 11q23.3–q24.3 in epithelial ovarian cancer associated with poor prognosis. Cancer Res 56:950–954

    PubMed  CAS  Google Scholar 

  39. Osada R, Horiuchi A, Kikuchi N et al (2007) Expression of hypoxia-inducible factor 1alpha, hypoxia-inducible factor 2alpha, and von Hippel–Lindau protein in epithelial ovarian neoplasms and allelic loss of von Hippel–Lindau gene: nuclear expression of hypoxia-inducible factor 1alpha is an independent prognostic factor in ovarian carcinoma. Hum Pathol 38:1310–1320

    Article  PubMed  CAS  Google Scholar 

  40. Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682

    Article  PubMed  CAS  Google Scholar 

  41. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    Article  PubMed  CAS  Google Scholar 

  42. Lee S, Garner EI, Welch WR et al (2007) Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma. Gynecol Oncol 106:311–317

    Article  PubMed  CAS  Google Scholar 

  43. Yasuda M, Miyazawa M, Fujita M et al (2008) Expression of hypoxia inducible factor-1alpha (HIF-1alpha) and glucose transporter-1 (GLUT-1) in ovarian adenocarcinomas: difference in hypoxic status depending on histological character. Oncol Rep 19:111–116

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a grant-in-aid for promotion of defense medicine from the Ministry of Defense, Japan (S.Y., H.T., and O.M.), and by a grant-in-aid for cancer research from the Ministry of Health, Labour, and Welfare, Japan (H.T.).

Conflict of interest statement

The authors declare no actual or potential conflicts of interest in this study.

Author information

Authors and Affiliations

  1. Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Sohei Yamamoto, Hitoshi Tsuda, Kozue Suzuki & Osamu Matsubara

  2. Department of Obstetrics and Gynecology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Masashi Takano

  3. Department of Laboratory Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Seiichi Tamai

  4. Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital, Tokyo, 104-0045, Japan

    Hitoshi Tsuda

Authors
  1. Sohei Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hitoshi Tsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kozue Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masashi Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seiichi Tamai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Osamu Matsubara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hitoshi Tsuda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamamoto, S., Tsuda, H., Suzuki, K. et al. An allelotype analysis indicating the presence of two distinct ovarian clear-cell carcinogenic pathways: endometriosis-associated pathway vs. clear-cell adenofibroma-associated pathway. Virchows Arch 455, 261–270 (2009). https://doi.org/10.1007/s00428-009-0816-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-009-0816-9

Keywords

Search

Navigation