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Genetik des familiären Brust- und Eierstockkrebses: Paneldiagnostik – Möglichkeiten und Grenzen

Genetic aspects of hereditary breast and ovarian cancer: options and limits

Zusammenfassung

Aktuelle Untersuchungen belegen, dass das hereditäre Mamma- und Ovarialkarzinom eine extreme genetische Heterogenität aufweist. Aktuell sind neben BRCA1 und BRCA2 bereits mehr als 20 Risikogene bekannt, die etwa ein Drittel aller familiären Fälle erklären können. Zusätzlich werden ständig neue polygene Komponenten identifiziert, die derzeit 16 % der gesamten genetischen Last bedingen. Das bedeutet, diese Varianten befinden sich zusätzlich zu hoch- oder moderat penetranten Mutationen in den Familien und modulieren die Penetranz.Gegenwärtig wird eine erweiterte BRCA-Diagnostik bereits in mehreren Ländern angeboten. Das Deutsche Konsortium Familiärer Brust- und Eierstockkrebs (GC-HBOC) hat z. B. für die Multigenanalyse das TruRisk™-Genpanel konsentiert, welches neben den 10 sog. „core genes“ (ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53) derzeit weitere noch zu validierende 24 Kandidatengene umfasst. Innerhalb des GC-HBOC wurde festgelegt, dass zunächst nur die Untersuchung der 10 core genes verpflichtend ist. Neben dem TruRisk™-Genpanel existieren zahlreiche kommerzielle Genpanels, wie beispielsweise das TruSight Cancer Panel (Fa. Illumina), welches 94 Gene abdeckt, oder die jeweils 26 Gene umfassenden BRCA Hereditary Cancer MASTRTM Plus (Fa. Multiplicom) und Myriad myRiskTM (Myriad Genetics) Panels. Der Einsatz der Paneldiagnostik ermöglicht, im Rahmen der molekulargenetischen Diagnostik bei Tumorprädispositionserkrankungen, die flexible Untersuchung der relevanten erblichen Risikofaktoren. Das heißt aber, dass die Panels ständig neuen Erkenntnissen angepasst werden, die zwangsläufig einerseits aus den laufenden klinischen Validierungsstudien und andererseits aus den initiierten „exom“- oder „whole-genome“ Sequenzierungen resultieren.

Abstract

Recent studies have documented the genetic heterogeneity of familial breast and ovarian cancer. In addition to BRCA1 and BRCA2, more than 20 risk genes for hereditary breast and ovarian cancer, explaining about one third of familial cases, have been identified so far. Additionally, polygenic factors have been discovered that may explain about 16 % of the genetic burden of BRCA1/2-negative cases. Today, routine diagnostics using gene panels in addition to BRCA1/2 testing is already offered in many countries, but sufficient information is available for only a few of the genes analyzed. Therefore, the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) compiled the TruRisk™ 34-gene panel, which contains 10 so-called “core genes” (ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53) in addition to 24 candidate genes. For members of the GC-HBOC, the analysis of the 10 core genes is obligatory. In addition to the TruRisk™ panel, several other gene panels are commercially available, e.g., the TruSight Cancer Panel (Illumina), which covers 94 genes, or the BRCA Hereditary Cancer MASTRTM Plus (Multiplicom) and Myriad MyRiskTM (Myriad Genetics), which comprise 26 genes each. All these gene panels include the core genes and are also applied in Germany.The use of panel diagnostics in the setting of molecular genetic testing for tumor predisposition disorders allows a reliable and flexible analysis of relevant risk factors. In contrast, exome or even whole genome sequencing is a powerful method of identifying further candidates quickly and cheaply. However, the determination of clinical consequences for mutations in novel genes requires comprehensive national and international validation studies.

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Notes

  1. 1.

    Das Breast Cancer Association Consortium (BCAC) vereint 65 nationale Studiengruppen und überschaut mehr als 100.000 (meist sporadische) Mammakarzinomfälle und mehr als 100.000 Kontrollprobanden.

  2. 2.

    Das Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) vereint 30 internationale Studiengruppen und überschaut derzeit über 36.000 Mutationsträgerinnen, davon sind mehr als 23.000 BRCA1- und mehr als 13.000 BRCA2-positiv.

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Correspondence to Alfons Meindl.

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Interessenkonflikt

A. Meindl, E. Hahnen weisen auf folgende Beziehungen hin: A. Meindl hat als Sachverständiger an Lynparza-Therapiestudien der Firma AstraZeneca teilgenommen und als Mitglied von Advisory Boards von AstraZeneca Honorare erhalten. E. Hahnen fungierte ebenfalls im Advisory Board von AstraZeneca. J. Ramser und J. Hauke geben an, dass kein Interessenkonflikt besteht.

Alle beschriebenen Untersuchungen am Menschen wurden mit Zustimmung der zuständigen Ethik-Kommission, im Einklang mit nationalem Recht sowie gemäß der Deklaration von Helsinki 1975 (in der aktuellen, überarbeiteten Fassung) durchgeführt. Von allen Patienten liegt eine Einverständniserklärung vor.

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Meindl, A., Ramser, J., Hauke, J. et al. Genetik des familiären Brust- und Eierstockkrebses: Paneldiagnostik – Möglichkeiten und Grenzen. medgen 27, 202–210 (2015). https://doi.org/10.1007/s11825-015-0048-0

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Schlüsselwörter

  • Erblicher Brust- und Eierstockkrebs
  • Paneldiagnostik
  • Risikogene
  • Multigenanalyse

Keywords

  • Hereditary breast and ovarian cancer
  • Panel diagnostics
  • Risk genes
  • Multigene analysis