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BRCA1 und BRCA2 − genetische und nichtgenetische Einflussfaktoren

BRCA1 and BRCA2 – genetic and non-genetic influencing factors for risk of disease

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Der Gynäkologe Aims and scope

Zusammenfassung

Hintergrund

Nicht für alle Trägerinnen einer Mutation in den Genen BRCA1 und BRCA2 liegt das lebenslange Erkrankungsrisiko für Brust- oder Eierstockkrebs gleich hoch. Bislang werden bei der Indikationsstellung zur Teilnahme an intensivierten Früherkennungs- und Nachsorgeprogrammen oder zur Durchführung einer prophylaktischen Operation keine risikomodifizierenden Faktoren berücksichtigt.

Fragestellung

Welche genetischen und nichtgenetischen Einflussfaktoren beeinflussen das Mammakarzinomrisiko von Anlageträgerinnen, und welche davon werden in den gebräuchlichen Risikoberechnungsprogrammen bereits berücksichtigt?

Ergebnisse und Diskussion

In genomweiten Assoziationstudien wurden Niedrigrisikovarianten gefunden und validiert. Einige davon modulieren das Risiko beim sporadischen und beim BRCA-assoziierten Mammakarzinom, es gibt für jeden Typ aber auch spezifische Varianten. Es gibt erste Studien, die vermuten lassen, dass Lebensstilfaktoren und reproduktive Faktoren das Risiko für BRCA-assoziierte Tumoren modulieren. Den bisherigen Rechenmodellen zur Schätzung des individuellen Risikos liegen eine variable Zahl hoch penetranter Gene und die Erhebung des Stammbaumes über 3 Generationen zugrunde. Zum Teil werden auch klinische Daten, wie Voroperationen, Tumorhistologie, Reproduktionsfaktoren oder „body mass index“ berücksichtigt. Die Erforschung der modifizierenden genetischen und nichtgenetischen Faktoren führt zur Erstellung eines umfassenden Risikoberechnungsprogramms. Dieses hat zum einen die Vermeidung von Übertherapie im Hinblick auf präventive Maßnahmen zum Ziel. Zum anderen bereitet die Kenntnis der individuellen Trigger einer potenziellen Brust- oder Eierstockkrebserkrankung den Weg für eine gezieltere Prävention von der medikamentösen Therapie bis hin zur Lebensstilintervention.

Abstract

Background

The lifelong risk for breast cancer and ovarian cancer differs among carriers of mutations in the BRCA1 and BRCA2 genes. Cancer risk is modulated by a multitude of genetic and non-genetic factors. For the decision on intensified surveillance or prophylactic mastectomy no risk modifiers are so far taken into account.

Aims

This article examines whether genetic and non-genetic factors modify the risk of breast cancer for BRCA1 and BRCA2 gene mutation carriers and which are integrated into currently used risk calculation programs.

Results and discussion

A number of genetic low risk variants have been identified and validated in genome-wide association studies. Several of these modify the risk of sporadic and BRCA-associated breast cancer and others are specific for each type. The results of initial studies suggest that lifestyle factors and reproductive history can also modify the risk of breast cancer for BRCA-associated tumors. Current risk calculation programs estimate the individual cancer risk based on assumptions on major genes with high penetrance and on the family pedigree over three generations. Some of these also take clinical data, such as previous operations, histopathological features of tumors, reproductive factors and body mass index into account but no explicit low risk variants. Ongoing research on modifying genetic and non-genetic risk factors aims to establish a more differentiated and comprehensive risk prediction model in order to prevent overtreatment with respect to preventive strategies. Additionally, knowledge on individual trigger mechanisms of potential breast or ovarian cancer might lead to targeted prevention by medicinal therapy and lifestyle interventions.

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Einhaltung ethischer Richtlinien

Interessenkonflikt. K. Kast und C. Fischer geben an, dass kein Interessenkonflikt besteht. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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Authors and Affiliations

  1. Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Carl Gustav Carus Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland

    K. Kast

  2. Institut für Humangenetik, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Deutschland

    C. Fischer

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Correspondence to K. Kast.

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Kast, K., Fischer, C. BRCA1 und BRCA2 − genetische und nichtgenetische Einflussfaktoren. Gynäkologe 47, 759–768 (2014). https://doi.org/10.1007/s00129-014-3350-z

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  • DOI: https://doi.org/10.1007/s00129-014-3350-z

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