Zusammenfassung
Die Inaktivierung von p16 und p14ARF wird als bedeutender Schritt der Tumorgenese des Oropharynxkarzinoms angesehen. Allelverluste in der Region dieser Gene werden in Mundschleimhautkarzinomen und deren Vorläuferläsionen angetroffen. Die vorliegende Studie sollte prüfen, in welchem Umfang Allelverluste bereits in Mundschleimhautleukoplakien auftreten und ob es anhand dieser Veränderungen möglich ist, Leukoplakien mit und ohne maligne Entartung zu unterscheiden. Darüber hinaus sollten geklärt werden, ob betroffene Leukoplakien Sequenzveränderungen der Gene p16 und p14ARF tragen, die eine Beeinträchtigung der Genfunktion bewirken können. Die Ergebnisse zeigten, dass „LOH“ (loss of heterozygosity) in Region der Gene p16 und p14ARF sowohl in Leukoplakien mit maligner Entartung als auch in klinisch entartungsfreien Leukoplakien auftreten, wobei sich die Allelverlusthäufigkeiten nicht signifikant unterscheiden. Insgesamt wurden in Leukoplakien seltener Allelverluste angetroffen als in den resultierenden Mundschleimhautkarzinomen (p < 0,05). Die Ergebnisse wiesen des Weiteren auf eine Häufung von LOH in dysplastischen Leukoplakien hin, ohne Signifikanzniveau zu erreichen. Langjähriges Tabakrauchen war mit signifikant gesteigerten Allelverlustraten assoziiert (p < 0,05). Die Gensequenzanalyse der Exonen 1α, 1β und 2 in Leukoplakien mit LOH ergab keine Veränderungen. Daraus schlussfolgern wir, dass Gen-Deletionen und Mutationen bei der Inaktivierung von p16 und p14ARF in Mundschleimhautleukoplakien eine untergeordnete Rolle spielen. Als frühes Ereignis der Karzinogenese treten sie in Leukoplakien mit und ohne maligne Entartung auf und sind als Einzelparameter daher ein unsicheres Bewertungskriterium des Entartungsrisikos. Sie sollten mit der Analyse anderer genetischer Faktoren, wie chromosomalen Methylierungsmustern und auch mit der histologischen Untersuchung kombiniert werden.
Abstract
The inactivation of p16 and p14ARF is considered to be an important step in the carcinogenesis of oropharygeal carcinomas. This consideration is supported by the observation of multiple allelic losses in the coding loci of chromosome 9p21 in squamous cell carcinomas and in dysplastic premalignant lesions. The present study hypothesized that comparable alterations already occur in leukoplakia, which are seen as potential predecessors of oral squamous cell carcinomas and that it is possible to differ leukoplakia with from leukoplakia without further malignant transformation. Furthermore we evaluated, whether such leukoplakia show sequence alterations in the genes p16 and p14ARF, which are capable to cause a limitation in gene function. The results show that the LOH pattern in genes p16 and p14ARF occur as well in leuplakia with malignant transformation as in leukoplakia, that do not show clinical alterations. The rate of allelic loss did not differ significantly. Overall, the incidence of allelic loss was lower in leuplakia compared to succeeding squamous-cell carcinomas (p < 0,05). The results further illustrated an increase in LOH patterns in dyplastic leukoplakia, without reaching statistical significance. Significant increases in allelic losses were found in heavy smokers, (p < 0,05). PCR analysis of the exons 1-alpha, exon 1-beta and exon 2 in leukoplakia, containing LOH patterns did not show genetic alterations. Thus we concluded, that gene deletion and gene mutation have a minor role in the inactivation process of p16 and p14ARF in oral leukoplakia. Representing an early process in carcinogenesis, gene deletion and mutation occur in leukoplakia with and without malignant transformation. Therefore, taken as a singular parameter they represent an uncertain criteria to assess the potential of malignant transformation. However they could provide information in combination with other genetic factors like chromosomal methylation patterns and histology.
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Nitsche, M., Koy, S., Mörz, M. et al. Untersuchung der Tumorsuppressoren p16INK4a und p14ARF in Mundschleimhautleukoplakien. Mund Kiefer GesichtsChir 11, 317–326 (2007). https://doi.org/10.1007/s10006-007-0086-0
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DOI: https://doi.org/10.1007/s10006-007-0086-0