Molekulare Pathogenese des Endometriumkarzinoms auf Basis eines dualistischen Modells

Zusammenfassung

In biologischer und klinischer Hinsicht unterscheidet man 2 unterschiedliche Typen des Endometriumkarzinoms, von denen einer östrogenabhängig (Typ I), der andere östrogenunabhängig (Typ II) ist. Typ-I-Karzinome haben eine günstige Prognose, kommen in jüngerem Alter vor, exprimieren meist Östrogen- (ÖR) und Progesteronrezeptoren (PR), sind häufig mit einer Endometriumhyperplasie assoziiert und entsprechen histopathologisch endometrioiden Karzinomen. Der Prototyp der Typ-II-Karzinome, die prognostisch ungünstig sind, in höherem Alter vorkommen, meist ÖR und PR negativ und mit atrophem Endometrium assoziiert sind, sind seröse Karzinome. Endometrioide und seröse Endometriumkarzinome unterscheiden sich signifikant bezüglich ihrer molekularen Veränderungen. Endometrioide Karzinome sind in bis zu 45 % mikrosatelliteninstabil (MIN-positiv), zeigen häufige K-ras- und PTEN-Mutationen, aber nur in ca. 10 % p53-Mutationen, einen Verlust der p16-Expression bzw. eine Her2/neu-Amplifikation. Andererseits zeigen seröse Karzinome in bis zu 90 % der Fälle p53-Mutationen, in 40-50 % eine fehlende p16-Expression bzw. in ca. 60 % eine Her2/neu-Amplifikation, wohingegen MIN- und K-ras-Mutationen fehlen. Familiäre Endometriumkarzinome im Rahmen des HNPCC treten 2 Jahrzehnte früher auf als sporadische Karzinome, sind vom endometrioiden Typ und meist infolge einer Keimbahnmutation der DNA-Reparaturgene MLH1 bzw. MSH2 MIN-positiv. Im Rahmen der Entstehung endometrioider Karzinome treten MIN- und PTEN-Mutationen früh auf, zum Teil bereits in der atypischen Hyperplasie, während p53-Mutationen, p16-Verlust und Her2/neu-Amplifikation späte Veränderungen im Rahmen der Progression darstellen. In der Enstehung seröser Karzinome sind p53-Mutationen wahrscheinlich frühe Veränderungen, da sie bereits im endometrialen intraepithelialen Karzinom (EIC), der möglichen Vorstufe, auftreten. Die zukünftige Forschung mit neuen technologischen Möglichkeiten wird neben der Entdeckung neuer bedeutender Gene die Interaktion der bisher bekannten Schlüsselgene und die Erfassung deren klinischer Bedeutung zum Ziel haben.

Summary

Sporadic endometrial carcinoma can be divided into two biologically and clinically distinctive subtypes of which one is estrogen-related (type I), the other estrogen-unrelated (type II). Type I carcinomas occur at younger age, express estrogen (ER) and progesterone receptors (PR), are frequently associated with endometrial hyperplasia and show a good prognosis. Type II carcinomas occur at older age, are negative for ER and PR, arise in the background of atrophic endometrium and show poor prognosis. Histologically, endometrioid carcinomas correspond to type I carcinomas whereas serous carcinoma is the prototype of type II carcinomas. Endometrioid and serous carcinomas are significantly different with respect to their molecular changes. Endometrioid carcinomas frequently show microsatellite instability (MIN), PTEN and K-ras mutation but infrequently p53 mutations, loss of p16 expression and her2/neu amplification, respectively. In contrast, serous carcinomas show a high frequency of p53 mutations and often loss of p16 expression whereas MIN and PTEN and K-ras mutations are uncommon. Familial endometrial carcinoma associated with HNPCC occur about two decades earlier than sporadic carcinomas, show endometrioid histology and are frequently MIN positiv due to germline mutations of mismatch repair genes (mostly MLH1 and MSH2). During the progression of endometrioid carcinoma PTEN mutations and MIN are considered early changes since they are present in a high frequency in atypical endometrial hyperplasia whereas p53 mutations, loss of p16 expression and her2/neu amplification are considered late events since they are predominantly found in poorly differentiated tumors. In contrast, p53 mutations are considered an early event in the pathogenesis of serous carcinoma occurring already in its putative precursor endometrial intraepithelial carcinoma (EIC). The future research will focus, besides the discovery of new relevant genes, on the interaction of known genes as well as their clinical relevance.

Schlüsselwörter

Endometriumkarzinom - molekulare Pathogenese - molekulare Veränderungen - Molekularpathologie

Key words

Endometrial carcinoma - Molecular pathogenesis - Molecular changes - Molecular Pathology

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