Skip to main content

Klinik und Genetik des familiären Brust- und Eierstockkrebses

Clinical course and genetics of hereditary breast and ovarian cancer

Zusammenfassung

Während mit der Entdeckung der Hochrisikogene „breast cancer 1“ (BRCA1) und „breast cancer 2“ (BRCA2) in den Jahren 1994/1995 die Erforschung des hereditären Mamma- und Ovarialkarzinoms zunächst beendet schien, belegen neuere Ergebnisse, dass das hereditäre Mamma- und Ovarialkarzinom eine extreme genetische Heterogenität aufweist. Die genetisch definierten Subtypen zeigen außerdem eine unterschiedliche phänotypische Ausprägung hinsichtlich der histopathologischen Charakteristika, des Krankheitsverlaufs und des Therapieansprechens. Dies erfordert eine Einbettung der Gendiagnostik in ein strukturiertes und standardisiertes Betreuungskonzept, das es erlaubt prospektive Daten zur Tumorinzidenz und zum Verlauf zu erfassen sowie in prospektiven Studien die Wertigkeit der verschiedenen diagnostischen, präventiven und neuen therapeutischen Optionen zu validieren. Das deutsche Konsortium widmet sich dieser Aufgabenstellung, um den betreffenden Familien effiziente Präventions- und Interventionsstrategien anbieten zu können. Dabei kommt der Zusammenarbeit mit der Selbsthilfe (http://www.BRCA-Netzwerk.de) mittlerweile eine große Bedeutung zu, die uns immer wieder vor Augen hält, wie wichtig es ist, den in diesem Artikel aufgeworfenen Fragestellungen nachzugehen.

Abstract

After the discovery of the high risk genes breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) in 1994/1995, research on hereditary breast and ovarian cancer appeared to be ended; however, more recent results show that hereditary breast and ovarian cancer are highly complex due to genetic heterogeneity. The genetically defined subtypes also show different phenotype expression concerning histopathological characteristics, course of the disease, and response to treatment. This requires that the genetic diagnostics be included in a structured and standardized care concept, which allows tumor incidence and disease course to be prospectively recorded and to validate the efficacy of various diagnostic, preventative, and new therapeutic options. The German consortium is dedicated to this cause in order to offer families affected efficient prevention and intervention strategies. Thereby, cooperation with the self-help group (http://www.BRCA-Netzwerk.de) has become of great importance by pointing out to us how important it is to address the open questions presented in this article.

This is a preview of subscription content, access via your institution.

Abb. 1
Abb. 2

Literatur

  1. 1.

    Gadzicki D, Meindl A, Schlegelberger B (2007) Erblicher Brust- und Eierstockkrebs. Medgen 19:202–209

    Article  CAS  Google Scholar 

  2. 2.

    King MC, Marks JH, Mandell JB, New York Breast Cancer Study G (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Antoniou AC, Cunningham AP, Peto J et al (2008) The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer 98:1457–1466

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Turnbull C, Ahmed S, Morrison J et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42:504–507

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Engert S, Wappenschmidt B, Betz B et al (2008) MLPA screening in the BRCA1 gene from 1,506 German hereditary breast cancer cases: novel deletions, frequent involvement of exon 17, and occurrence in single early-onset cases. Hum Mutat 29:948–958

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Goldgar DE, Easton DF, Deffenbaugh AM et al (2004) Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75:535–544

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Bosse K, Rhiem K, Wappenschmidt B et al (2006) Screening for ovarian cancer by transvaginal ultrasound and serum CA125 measurement in women with a familial predisposition: a prospective cohort study. Gynecol Oncol 103:1077–1082

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Meindl A, Ditsch N, Kast K et al (2011) Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Dtsch Arztebl Int 108:323–330

    PubMed  Google Scholar 

  9. 9.

    Domchek SM, Friebel TM, Singer CF et al (2010) Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304:967–975

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Lakhani SR, Reis-Filho JS, Fulford L et al (2005) Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11:5175–5180

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Bolton KL, Chenevix-Trench G, Goh C et al (2012) Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307:382–390

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Graeser MK, Engel C, Rhiem K et al (2009) Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27:5887–5892

    PubMed  Article  Google Scholar 

  13. 13.

    Rhiem K, Engel C, Graeser M et al (2012) The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study. Breast Cancer Res 14:R156

    PubMed  Article  Google Scholar 

  14. 14.

    Rhiem K, Wappenschmidt B, Bosse K et al (2009) Platinum sensitivity in a BRCA1 mutation carrier with advanced breast cancer. Clin Oncol 21:448–450

    Article  CAS  Google Scholar 

  15. 15.

    Tutt A, Robson M, Garber JE et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Helleday T, Bryant HE, Schultz N (2005) Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 4(9):1176-8

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Liede A, Karlan BY, Narod SA (2004) Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22:735–742

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Antoniou AC, Beesley J, McGuffog L et al (2010) Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70:9742–9754

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Meindl A, Hellebrand H, Wiek C et al (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42:410–414

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Coulet F, Fajac A, Colas C et al (2013) Germline RAD51C mutations in ovarian cancer susceptibility. Clin Genet 83:332-6

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Loveday C, Turnbull C, Ruark E et al (2012) Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet 44:475–476 (author reply 476)

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Osorio A, Endt D, Fernandez F et al (2012) Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 21:2889–2898

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Walsh T, Casadei S, Lee MK et al (2011) Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A108:18032–18037

    Article  Google Scholar 

  24. 24.

    Loveday C, Turnbull C, Ramsay E et al (2011) Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43:879–882

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Wickramanyake A, Bernier G, Pennil C et al (2012) Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol 127:552–555

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Goldgar DE, Healey S, Dowty JG et al (2011) Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res 13:R73

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Jones S, Hruban RH, Kamiyama M et al (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324:217

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Knappskog S, Chrisanthar R, Lokkevik E et al (2012) Low expression levels of ATM may substitute for CHEK2/TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer. Breast Cancer Res 14:R47

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Engel C, Loeffler M, Steinke V et al (2012) Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol 30:4409–4415

    PubMed  Article  Google Scholar 

  30. 30.

    Steinke V, Vogt S, Aretz S (2010) Klinik und Genetik des familiären Darmkrebses. Medgen 22:265–281

    Article  Google Scholar 

  31. 31.

    Neveling K, Hoischen A (2012) Exom-Sequenzierung zur Identifizierung von Krankheitsgenen Medgen 24:4-11

    Google Scholar 

  32. 32.

    Park DJ, Lesueur F, Nguyen-Dumont T et al (2012) Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 90:734–739

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Ruark E, Snape K, Humburg P et al (2013) Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493:406–410

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Thompson ER, Doyle MA, Ryland GL et al (2012) Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet 8:e1002894

    PubMed  Article  CAS  Google Scholar 

Download references

Interessenkonflikt

Prof. Dr. Meindl, Prof. Dr. Schmutzler und PD Dr. Rhiem erhielten Honorare für die Teilnahme an Advisory Board Treffen der Fa. Astra Zeneca. Prof. Dr. Schmutzler erhielt des Weiteren Honorare für die Teilnahme an Advisory Board Treffen der Firmen Sanofi Aventis und Eisai, Teilnahmegebührenerstattung für den ASCO-Kongress von den Firmen Astra Zeneca, Roche, Sanofi Aventis, Glaxo, Vortragshonorare von Astra Zeneca, Sanofi Aventis und Roche sowie Studiengelder für klinische Studien der Firmen Astra Zeneca, Sanofi Aventis, Siemens Medical Solutions, Amgen. Dr. Kast erhielt eine Teilnahmegebührenerstattung für den ASCO- und SABCS-Kongress von den Firmen Roche und Glaxo, Vortragshonorare von Amgen, Sanofi Aventis, Glaxo und Roche.

Author information

Affiliations

Authors

Corresponding author

Correspondence to A. Meindl.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Meindl, A., Rhiem, K., Engel, C. et al. Klinik und Genetik des familiären Brust- und Eierstockkrebses. medgen 25, 259–277 (2013). https://doi.org/10.1007/s11825-013-0390-z

Download citation

Schlüsselwörter

  • Neoplasien
  • Genetik
  • Genetische Beratung
  • Sekundärprävention
  • Prognose

Keywords

  • Neoplasms
  • Genetics
  • Genetic counseling
  • Secondary prevention
  • Prognosis