Molekulare Mechanismen der Schilddrüsentumorgenese

Zusammenfassung

Schilddrüsenknoten liegen in bis zu 30 % der deutschen Bevölkerung vor und zählen damit zu den häufigsten endokrinologischen Erkrankungen. Schilddrüsenknoten sind außerordentlich heterogen. Die Entstehung von Tumoren mit unterschiedlichen funktionellen und morphologischen Eigenschaften aus einer einzigen Vorläuferzelle ist ein besonderes Charakteristikum der Schilddrüse (SD) und wird durch spezifische genetische Veränderungen verursacht. Bei etwa 60–70 % der differenzierten SD-Karzinome sind Mutationen in bekannten Genen nachweisbar, die über konstitutive Signaltransduktionsaktivierung den Phänotyp des Karzinoms determinieren. In sporadischen papillären SD-Karzinomen (PTCs) liegen BRAF- (oder seltener RAS-)Mutationen vor, während chromosomale Rearrangements (RET, TRK, AKAP9 / BRAF) vorrangig in strahleninduzierten PTCs auftreten. Diese genetischen Veränderungen führen zur MAPKinasen-Aktivierung. In follikulären SD-Karzinomen (FTC) liegen RAS-Mutationen oder PAX8 / PPARγ-Rearrangements vor, diese sind allerdings auch in einem Teil der follikulären Adenome (FA) nachgewiesen. Des Weiteren zeigen aktuelle Arbeiten, dass eine Aktivierung der PI3K / AKT-Signaltransduktion in follikulären SD-Tumoren besonders häufig ist. Undifferenzierte (anaplastische) Schilddrüsenkarzinome (ATC) weisen genetische Merkmale von FTC oder PTC auf und darüber hinaus eine drastische Aktivierung mehrerer Tyrosinkinasekaskaden (Überexpression oder Mutationen im PI3K und MAPKinase-Pathway). Dies unterstreicht das Konzept einer sequenziellen Entwicklung eines ATC aus einem differenzierten SD-Karzinom, als dessen Triggermechanismus die p53-Inaktivierung angesehen wird.

Mit Ausnahme der SD-Autonomie, die durch konstitutive cAMP-Aktivierung (TSHR oder seltener Gs-α-Protein-Mutationen) verursacht wird, ist die molekulare Pathogenese von benignen SD-Tumoren, insbesondere der kalten Knoten, noch ungeklärt.

Abstract

Thyroid nodules are the most frequent endocrine disorder and occur in approximately 30 % of the German population. Thyroid nodular disease constitutes a very heterogeneous entity. A striking diversity of possible functional and morphological features of a thyroid tumour derived from the same thyroid ancestor cell, is a hallmark of thyroid tumorigenesis and is due to specific genetic alterations. Defects in known candidate genes can be found in up to 70 % of differentiated thyroid carcinomas and determine the respective cancer phenotype. Papillary thyroid cancers (PTC) harbour BRAF (or much less frequently RAS) mutations in sporadically occurring tumours, while radiation-induced PTC display chromosomal rearrangements such as RET, TRK, APR9 / BRAF. These genetic events results in constitutive MAPKinase activation. Follicular thyroid cancers (FTC) harbour RAS mutations or PAX8 / PPARγ rearrangements, both of which, however have also been identified in follicular adenoma. In addition, recent studies show, that activation of PI3K / AKT signalling occurs with high frequency in follicular thyroid tumours. Undifferentiated (anaplastic) thyroid cancers (ATC) display genetic features of FTC or PTC, in addition to aberant activation of multiple tyrosinkinase pathways (overexpression or mutations in PI3K and MAPK pathways). This underscores the concept of a sequential evolution of ATC from differentiated thyroid cancer, a process widely conceived to be triggered by p53 inactivation. In contrast, the molecular pathogenesis of benign thyroid tumours, in particular cold thyroid nodules is less known, except for toxic thyroid nodules, which arise from constitutive activation of cAMP signalling, predominantly through TSHR mutations.

noduläre Schilddrüsenerkrankungen - Schilddrüsenkarzinome - benigner Schilddrüsenknoten - Differenzialdiagnostik

nodular thyroid disease - thyroid carcinoma - benign thyroid nodules - differential diagnosis

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