Hereditäres Mamma- und Ovarialkarzinom - ein Update Teil I - molekulare Grundlagen, Tumorrisikoberatung und Risikoberechnung

Zusammenfassung

Das Mammakarzinom ist bei weitem die häufigste Karzinomdiagnose der Frau. Das kumulative Risiko für eine Erkrankung beträgt 10 % bis zum 80. Lebensjahr. Die Risikofaktoren für die Mammakarzinomentstehung sind vielfältig. Ein wesentlicher Risikofaktor ist die familiäre Belastung. 5 - 10 % aller und 25 - 40 % der Mammakarzinome vor dem 35. Lebensjahr sind genetisch bedingt. 3 - 8 % aller Mammakarzinome und 15 - 20 % aller familiären Mammakarzinome sind durch BRCA1/2-Mutationen bedingt. Das Ovarialkarzinom basiert in 10 % der Fälle auf einer genetischen Prädisposition. Ca. 80 % aller Familien mit familiärer Ovarialkarzinombelastung sind mit BRCA1-Mutationen und ca. 15 % mit BRCA2-Mutationen assoziiert. Eine Anzahl weiterer Gene mit Assoziation zum familiären Mamma- und Ovarialkarzinomsyndrom wurden bereits in den letzten Jahren identifiziert (Hoch- und Niedrig-Penetranz-Gene, risk modifier). Dieses zeigt, dass es sich um ein komplexes Phänomen handelt, das vermutlich multifaktoriell bedingt ist.

BRCA1/2-assoziierte Karzinome zeigen spezielle pathologische Charakteristika, insbesondere eine hohe Mitoserate, erhöhte Pleomorphie, vermehrte Proliferationsraten, niedrige Differenzierung und ein vermehrtes Auftreten von Grad-III-Tumoren. Zudem ist in BRCA1-assoziierten Karzinomen die Östrogen- und Progesteronrezeptorexpression gegenüber sporadischen Karzinomen reduziert. Bei den hereditären und sporadischen Ovarialkarzinomen sind die meisten klinisch-pathologischen Charakteristika ähnlich.

Im Rahmen spezieller interdisziplinärer Tumorrisikosprechstunden können Frauen mit familiärer Belastung beraten und betreut werden. Eine genetische Analyse kann angeboten werden. Risikoberechnungsprogramme können das Risiko näher definieren. Es existiert eine Anzahl an verfügbaren Berechnungsmodellen, welche klinische Entscheidungen bezüglich genetischer Testung, Prävention, prophylaktischer Chirurgie und Früherkennung unterstützen können.

Abstract

Breast cancer is the most frequent carcinoma in women. The cumulative risk for disease is 10 % up to the age of 80. The risk factors for breast cancer are manifold. An important factor is the familial history of breast and ovarian cancer. 5 - 10 % of all breast cancer cases and 25 - 40 % of breast cancer cases prior to the age of 35 have a hereditary origin. BRCA1/2 mutations are responsible for 3 - 8 % of all and 15 - 20 % of familial breast cancer cases. 10 % of ovarian cancer cases have a genetic predisposition. About 80 % (15 %) of all families with a history of ovarian cancer cases are associated with BRCA1 (BRCA2) mutations. A number of other genes, which are associated with familial breast and ovarian cancer syndrome, have been identified in the last years (high and low penetrance genes, risk modifier). This demonstrates that the syndrome is a complex phenomenon.

BRCA1/2-associated breast carcinoma present special pathological characteristics. They have a higher mitotic rate, higher pleomorphy, higher proliferation rates, a lower differentiation and are more often associated with grade III tumours. Moreover, BRCA1-associated carcinoma show no expression of the estrogen and progesteron receptor. Hereditary and sporadic ovarian cancer presents similar pathological characteristics. In the context of interdisciplinary genetic cancer clinics, women at risk can be informed and advised. Women who fullfil the inclusion criteria for genetic testing can have access to analysis.

Risk calculation programs can define the risk. There are several calculation models which assist in making decisions for genetic testing, chemoprevention, prophylactical surgery and intensified early cancer detection programs.

Schlüsselwörter

Hereditäres Mammakarzinom - hereditäres Ovarialkarzinom - BRCA - familiäres Risiko - prädiktive genetische Testung - Risikoberechnung

Key words

Hereditary breast cancer - hereditary ovarian cancer - BRCA - familial risk - predictive genetic testing - risk estimation

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