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Molekularpathologie der epithelialen Ovarialneoplasien

Von der Phänotyp-Genotyp-Korrelation zu neuen Ansatzpunkten in Diagnostik und Therapie

Molecular pathology of epithelial ovarian neoplasias: from the phenotype-genotype correlation to new targets in diagnostics and therapy

  • Schwerpunkt: Ovarialtumoren
  • Published:
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Zusammenfassung

Trotz großer morphologischer Vielfalt lassen sich bei Ovarialkarzinomen aufgrund von pathogenetischen Gemeinsamkeiten 2 Gruppen unterscheiden. In der Zusammenschau von klinischen, pathologischen und molekularen Parametern zeigt sich einerseits eine relativ große Gruppe von Tumoren mit schrittweiser Entstehung aus gutartigen Vorstufen über Borderline-Tumoren hin zu invasiven Karzinomen (Typ I). Je nach morphologischem Typ kommen dabei unterschiedliche Genveränderungen zum Tragen. Dazu gehören Mutationen in KRAS und BRAF in serösen Borderline-Tumoren und „low grade“ serösen Karzinomen. Mutationen in KRAS finden sich auch häufig in muzinösen Borderline-Tumoren und muzinösen Karzinomen. Bei endometrioiden Tumoren findet man vor allem Mutationen in Komponenten der Wnt-Signalkaskade, in PTEN oder in Genen, welche eine Gruppe von Proteinen für DNA-Reparaturmechanismen kodieren („mismatch repair“). Zur zweiten, größeren Gruppe (Typ II) gehören Tumoren mit De-novo-Entstehung von hochmalignen Karzinomen. Hierbei handelt es sich zumeist um die konventionellen, mäßig bis gering differenzierten serösen Karzinome und undifferenzierte Karzinome. Diese sind insbesondere durch häufige Mutationen von p53 und komplexe chromosomale Alterationen gekennzeichnet. Es ist zu erwarten, dass kombinierte Analysen von morphologischen Parametern, genetischen Veränderungen, Genexpressions- und Proteinmustern in diesen beiden Gruppen von Tumoren neue Ansatzpunkte für Diagnostik und Therapie identifizieren werden.

Abstract

Despite the fact that ovarian carcinomas are phenotypically heterogeneous, they can be divided into two main groups with common pathogenetic mechanisms. Based on clinical, pathological and molecular parameters, a relatively large group of tumors can be distinguished with stepwise development from benign precursors and borderline tumors to invasive carcinomas (type I). Depending on the morphological phenotype, characteristic genetic changes can be observed, such as mutations in KRAS and BRAF in serous borderline tumors and low-grade serous carcinomas. Mutations in KRAS are also frequently detected in mucinous borderline tumors and mucinous carcinomas. The group of endometrioid tumors is characterized by mutations in components of the Wnt-signal transduction pathway and PTEN or microsatellite instability. The second large group of tumors (type II) includes tumors with “de novo” development of highly malignant carcinomas such as the conventional (moderately to poorly differentiated) high-grade serous carcinomas, undifferentiated carcinomas and malignant mixed mesodermal tumors. These tumors are associated with frequent mutations in p53 and complex chromosomal alterations. In the future, the combined analysis of morphological parameters, genetic changes, gene-expression profiling and protein data will reveal possible diagnostic and therapeutic targets for ovarian carcinomas.

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Literatur

  1. Abeysinghe HR, Cedrone E, Tyan T et al. (1999) Amplification of C-MYC as the origin of the homogeneous staining region in ovarian carcinoma detected by micro-FISH. Cancer Genet Cytogenet 114: 136–143

    Article  PubMed  Google Scholar 

  2. Anand N, Murthy S, Amann G et al. (2002) Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nat Genet 31: 301–305

    PubMed  Google Scholar 

  3. Anzick SL, Kononen J, Walker RL et al. (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277: 965–968

    Article  PubMed  Google Scholar 

  4. Bjorge T, Lie AK, Hovig E et al. (2004) BRCA1 mutations in ovarian cancer and borderline tumours in Norway: a nested case-control study. Br J Cancer 91: 1829–1834

    Article  PubMed  Google Scholar 

  5. Bonome T, Lee JY, Park DC et al. (2005) Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Res 65: 10602–10612

    Article  PubMed  Google Scholar 

  6. Chamorro MN, Schwartz DR, Vonica A et al. (2005) FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J 24: 73–84

    Article  PubMed  Google Scholar 

  7. Cheng KW, Lahad JP, Kuo WL et al. (2004) The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med 10: 1251–1256

    Article  PubMed  Google Scholar 

  8. Diebold J (1998) Molekulargenetik der epithelialen Ovarialneoplasien: Korrelationen zum Phänotyp und biologischen Verhalten [Molecular genetics of epithelial ovarian neoplasms: correlations with phenotype and biological behavior]. Pathologe 19: 95–103

    Article  PubMed  Google Scholar 

  9. Diebold J (1999) Molecular genetics of ovarian carcinomas. Histol Histopathol 14: 269–277

    PubMed  Google Scholar 

  10. Diebold J, Mosinger K, Peiro G et al. (2000) 20q13 and cyclin D1 in ovarian carcinomas. Analysis by fluorescence in situ hybridization. J Pathol 190: 564–571

    Article  PubMed  Google Scholar 

  11. Diebold J, Suchy B, Baretton GB et al. (1996) DNA ploidy and MYC DNA amplification in ovarian carcinomas. Correlation with p53 and bcl-2 expression, proliferative activity and prognosis. Virchows Arch 429: 221–227

    Article  PubMed  Google Scholar 

  12. Gemignani ML, Schlaerth AC, Bogomolniy F et al. (2003) Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol 90: 378–381

    Article  PubMed  Google Scholar 

  13. Gilks CB, Vanderhyden BC, Zhu S et al. (2005) Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling. Gynecol Oncol 96: 684–694

    Article  PubMed  Google Scholar 

  14. Gras E, Catasus L, Arguelles R et al. (2001) Microsatellite instability, MLH-1 promoter hypermethylation, and frameshift mutations at coding mononucleotide repeat microsatellites in ovarian tumors. Cancer 92: 2829–2836

    Article  PubMed  Google Scholar 

  15. Hauptmann S, Denkert C, Koch I et al. (2002) Genetic alterations in epithelial ovarian tumors analyzed by comparative genomic hybridization. Hum Pathol 33: 632–641

    Article  PubMed  Google Scholar 

  16. Hirasawa A, Saito-Ohara F, Inoue J et al. (2003) Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res 9: 1995–2004

    PubMed  Google Scholar 

  17. Hogdall EV, Christensen L, Kjaer SK et al. (2003) Distribution of HER-2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma: from the Danish MALOVA Ovarian Cancer Study. Cancer 98: 66–73

    Article  PubMed  Google Scholar 

  18. Ichikawa Y, Nishida M, Suzuki H et al. (1994) Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors. Cancer Res 54: 33–35

    PubMed  Google Scholar 

  19. Iwabuchi H, Sakamoto M, Sakunaga H et al. (1995) Genetic analysis of benign, low-grade, and high-grade ovarian tumors. Cancer Res 55: 6172–6180

    PubMed  Google Scholar 

  20. Kiechle M, Jacobsen A, Schwarz-Boeger U et al. (2001) Comparative genomic hybridization detects genetic imbalances in primary ovarian carcinomas as correlated with grade of differentiation. Cancer 91: 534–540

    Article  PubMed  Google Scholar 

  21. Lassus H, Leminen A, Vayrynen A et al. (2004) ERBB2 amplification is superior to protein expression status in predicting patient outcome in serous ovarian carcinoma. Gynecol Oncol 92: 31–39

    Article  PubMed  Google Scholar 

  22. Meinhold-Heerlein I, Bauerschlag D, Hilpert F et al. (2005) Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential. Oncogene 24: 1053–1065

    Google Scholar 

  23. Obata K, Morland SJ, Watson RH et al. (1998) Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58: 2095–2097

    PubMed  Google Scholar 

  24. Partheen K, Levan K, Osterberg L et al. (2004) Analysis of cytogenetic alterations in stage III serous ovarian adenocarcinoma reveals a heterogeneous group regarding survival, surgical outcome, and substage. Genes Chromosomes Cancer 40: 342–348

    Article  PubMed  Google Scholar 

  25. Rebbeck TR, Lynch HT, Neuhausen SL et al. (2002) Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346: 1616–1622

    Article  PubMed  Google Scholar 

  26. 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  Google Scholar 

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

    PubMed  Google Scholar 

  28. Schraml P, Schwerdtfeger G, Burkhalter F et al. (2003) Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma. Am J Pathol 163: 985–992

    PubMed  Google Scholar 

  29. Schwartz DR, Kardia SL, Shedden KA et al. (2002) Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res 62: 4722–4729

    PubMed  Google Scholar 

  30. Seidman JD, Horkayne-Szakaly I, Haiba M et al. (2004) The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 23: 41–44

    Article  PubMed  Google Scholar 

  31. Seidman JD, Russell P, Kurman RJ (2002) 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

  32. Shayesteh L, Lu Y, Kuo WL et al. (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21: 99–102

    Article  PubMed  Google Scholar 

  33. Shih I, Kurman RJ (2004) Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164: 1511–1518

    PubMed  Google Scholar 

  34. Singer G, Kurman RJ, Chang HW et al. (2002) Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol 160: 1223–1228

    PubMed  Google Scholar 

  35. Singer G, Stohr R, Cope L et al. (2005) Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 29: 218–224

    Article  PubMed  Google Scholar 

  36. Smith Sehdev AE, Sehdev PS, Kurman RJ (2003) Noninvasive and invasive micropapillary (low-grade) serous carcinoma of the ovary: a clinicopathologic analysis of 135 cases. Am J Surg Pathol 27: 725–736

    Article  PubMed  Google Scholar 

  37. Staebler A, Heselmeyer-Haddad K, Bell K et al. (2002) Micropapillary serous carcinoma of the ovary has distinct patterns of chromosomal imbalances by comparative genomic hybridization compared with atypical proliferative serous tumors and serous carcinomas. Hum Pathol 33: 47–59

    Article  PubMed  Google Scholar 

  38. Staebler A, Karberg B, Behm J et al. (2006) Chromosomal losses of regions on 5q and lack of high-level amplifications on 8q24 are associated with favorable prognosis for ovarian serous carcinoma. Genes Chromosomes Cancer 45: 905–917

    Article  PubMed  Google Scholar 

  39. Suzuki S, Moore DH, Ginzinger DG et al. (2000) An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer. Cancer Res 60: 5382–5385

    PubMed  Google Scholar 

  40. Werness BA, Ramus SJ, DiCioccio RA et al. (2004) Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry. Int J Gynecol Pathol 23: 29–34

    Article  PubMed  Google Scholar 

  41. Wu R, Zhai Y, Fearon ER et al. (2001) Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res 61: 8247–8255

    PubMed  Google Scholar 

  42. Zhang L, Yang N, Huang J et al. (2005) Transcriptional coactivator Drosophila eyes absent homologue 2 is up-regulated in epithelial ovarian cancer and promotes tumor growth. Cancer Res 65: 925–932

    PubMed  Google Scholar 

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Staebler, A., Diebold, J. Molekularpathologie der epithelialen Ovarialneoplasien. Pathologe 28, 180–186 (2007). https://doi.org/10.1007/s00292-007-0910-1

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