Advertisement

Der Pathologe

, Volume 38, Issue 2, pp 117–126 | Cite as

BRCA-Diagnostik an Ovarialkarzinomen

Molekulare Tumortestung seit Einführung der PARP-Inhibitortherapie
CME

Zusammenfassung

Jährlich erkranken etwa 9000 Frauen in Deutschland neu am Ovarialkarzinom. Der häufigste Subtyp ist das seröse „High-grade“-Ovarialkarzinom. Ein Teil der Ovarialkarzinome ist assoziiert mit einer Mutation von BRCA1 oder BRCA2 („breast and ovarian cancer susceptibility gen“); dies sind hochpenetrante Tumorsuppressorgene mit autosomalem Erbgang und Schlüsselgene in der DNA-Reparatur. Im überwiegenden Prozentsatz liegt eine Keimbahnmutation vor, in einem geringeren Prozentsatz jedoch eine rein somatische BRCA-Mutation. BRCA1- oder BRCA2-mutierte Tumoren zeigen eine deutliche Verbesserung des progressionsfreien Überlebens unter einer Therapie mit Poly(Adenosindiphosphat-Ribose)-Polymerase(PARP)-Inhibitoren. Im Jahr 2015 wurde der erste PARP-Inhibitor für die Therapie des BRCA-mutierten rezidivierten serösen „High-grade“-Ovarialkarzinoms zugelassen. Die BRCA-Mutationsanalyse kann an formalinfixiertem paraffineingebettetem („formalin-fixed, paraffin-embedded“, FFPE) Tumorgewebe innerhalb weniger Tage durchgeführt werden.

Schlüsselwörter

DNA High-grade seröses Ovarialkarzinom Mutationsanalyse Olaparib FFPE-Material 

BRCA diagnostics of ovarian cancer

Molecular tumor testing since the introduction of PARP inhibitor therapy

Abstract

Approximately 9000 women are diagnosed with ovarian cancer in Germany each year. The most common subtype is high-grade serous ovarian cancer. A relevant proportion of these tumors are associated with mutations in the breast and ovarian cancer susceptibility genes (BRCA1 and BRCA2) representing highly penetrant tumor suppressor genes with autosomal inheritance and play a crucial role in DNA repair mechanisms. These patients have predominantly germline mutations and less frequently have somatic BRCA mutations. Tumors harboring BRCA mutations show a significant improvement in progression-free survival under therapy with poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. In 2015 the first PARP inhibitor was approved for the therapy of high-grade serous ovarian cancer with BRCA mutations. Mutation analysis can be performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue within a few days.

Keywords

DNA High-grade serous ovarian cancer Mutational analysis Olaparib FFPE material 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

H. Löser, C. Heydt, R. Büttner und B. Markiefka geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
  2. 2.
  3. 3.
    Trimbos B, Timmers P, Pecorelli S et al (2010) Surgical staging and treatment of early ovarian cancer: long-term analysis from a randomized trial. J Natl Cancer Inst 102:982–987CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Du Bois A, Reuss A, Pujade-Lauraine E et al (2009) Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 115:1234–1244CrossRefPubMedGoogle Scholar
  5. 5.
    Ledermann JA, Harter P, Gourley C et al (2016) Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 17:1579–1589CrossRefPubMedGoogle Scholar
  6. 6.
    Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71CrossRefPubMedGoogle Scholar
  7. 7.
    Wooster R, Bignell G, Lancaster J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792CrossRefPubMedGoogle Scholar
  8. 8.
    Lord CJ, Ashworth A (2016) BRCAness revisited. Nat Rev Cancer 16:110–120CrossRefPubMedGoogle Scholar
  9. 9.
    Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12:801–817CrossRefPubMedGoogle Scholar
  10. 10.
    Bougie O, Weberpals JI (2011) Clinical considerations of BRCA1- and BRCA2-mutation carriers: a review. Int J Surg Oncol 2011:374012PubMedPubMedCentralGoogle Scholar
  11. 11.
    Garcia-Casado Z, Romero I, Fernandez-Serra A et al (2011) A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. BMC Med Genet 12:134CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Farmer H, Mccabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921CrossRefPubMedGoogle Scholar
  13. 13.
    Underhill C, Toulmonde M, Bonnefoi H (2011) A review of PARP inhibitors: from bench to bedside. Ann Oncol 22:268–279CrossRefPubMedGoogle Scholar
  14. 14.
    Park SR, Chen A (2012) Poly(Adenosine diphosphate-ribose) polymerase inhibitors in cancer treatment. Hematol Oncol Clin North Am 26:649–670CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Turner NC, Lord CJ, Iorns E et al (2008) A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J 27:1368–1377CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Helleday T (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol 5:387–393CrossRefPubMedGoogle Scholar
  17. 17.
    Cancer Genome Atlas Research N (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615CrossRefGoogle Scholar
  18. 18.
    Hennessy BT, Timms KM, Carey MS et al (2010) Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 28:3570–3576CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Meindl A, Ditsch N, Kast K et al (2011) Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Dtsch Arztebl Int 108:323–330PubMedPubMedCentralGoogle Scholar
  20. 20.
    Nielsen FC, Van Overeem Hansen T, Sorensen CS (2016) Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer 16:599–612CrossRefPubMedGoogle Scholar
  21. 21.
    Hammond ME, Hayes DF, Dowsett M et al (2010) American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chen H, Luthra R, Goswami RS et al (2015) Analysis of pre-analytic factors affecting the success of clinical next-generation sequencing of solid organ malignancies. Cancers (Basel) 7:1699–1715CrossRefGoogle Scholar
  23. 23.
    Heydt C, Fassunke J, Kunstlinger H et al (2014) Comparison of pre-analytical FFPE sample preparation methods and their impact on massively parallel sequencing in routine diagnostics. PLOS ONE 9:e104566CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hadd AG, Houghton J, Choudhary A et al (2013) Targeted, high-depth, next-generation sequencing of cancer genes in formalin-fixed, paraffin-embedded and fine-needle aspiration tumor specimens. J Mol Diagn 15:234–247CrossRefPubMedGoogle Scholar
  25. 25.
    Plon SE, Eccles DM, Easton D et al (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29:1282–1291CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Martelotto LG, Ng CK, De Filippo MR et al (2014) Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations. Genome Biol 15:484CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sharan SK, Morimatsu M, Albrecht U et al (1997) Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386:804–810CrossRefPubMedGoogle Scholar
  28. 28.
    Wu LC, Wang ZW, Tsan JT et al (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14:430–440CrossRefPubMedGoogle Scholar
  29. 29.
    Ewald IP, Ribeiro PL, Palmero EI et al (2009) Genomic rearrangements in BRCA1 and BRCA2: a literature review. Genet Mol Biol 32:437–446CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Endris V, Stenzinger A, Pfarr N et al (2016) NGS-based BRCA1/2 mutation testing of high-grade serous ovarian cancer tissue: results and conclusions of the first international round robin trial. Virchows Arch 468:697–705CrossRefPubMedGoogle Scholar
  31. 31.
    Ellison G, Luke S, Ahdesmäki M et al (2017) An evaluation of challenges to developing tumour BRCA1 and BRCA2 testing methodologies for clinical practice (submitted)Google Scholar

Copyright information

© Springer Medizin Verlag GmbH 2017

Authors and Affiliations

  • H. Löser
    • 1
  • C. Heydt
    • 1
  • R. Büttner
    • 1
  • B. Markiefka
    • 1
  1. 1.Institut für PathologieUniklinik KölnKölnDeutschland

Personalised recommendations