Genomische Aberrationen beim invasiven Zervixkarzinom

Zusammenfassung

Fragestellung

Zervixkarzinome sind meistens Plattenepithelkarzinome, während Adenokarzinome seltener auftreten. Spezifische genomische Veränderungen sind verantwortlich für die Karzinogenese und Tumorprogression von Zervixkarzinomen. Der Zusammenhang zwischen Genotyp und Phänotyp beim Zervixkarzinom ist bis heute unklar.

Material und Methodik

Die Methode der Comparative Genomic Hybridization wurde verwendet, um in 62 Plattenepithel- und 22 Adenokarzinomen des klinischen Stadiums FIGO IB nach DNS-Sequenzveränderungen zu suchen. Zusätzlich wurde der HercepTest^TM angewandt, um immunhistochemisch die Expression von HER-2/neu beim Adenokarzinom zu beurteilen.

Ergebnisse

In beiden Tumorarten waren DNS-Sequenzverluste am häufigsten auf 4 q, Xq und 18 q zu finden. DNS-Sequenzverluste waren die häufigsten Alterationen beim Plattenepithelkarzinom, während DNS-Sequenzvermehrungen auf 17 q die häufigste Alteration beim Adenokarzinom darstellten. HER-2/neu Überexpression wurde nur in 2 Adenokarzinomen festgestellt. Die Gesamtzahl der DNS-Aberrationen pro Tumor und die Anzahl von DNS-Sequenzverlusten pro Tumor waren signifikant assoziiert mit dem tumorspezifischen Überleben beim Plattenepithelkarzinom. Sequenzverluste auf den Chromosomen 11 p und 18 q waren signifikant assoziiert mit einer schlechten Prognose beim Plattenepithelkarzinom ohne Lymphknotenmetastasen. Analog zum Plattenepithelkarzinom sind DNS-Sequenzverluste des Chromosoms 18 q auch beim Adenokarzinom eindeutig assoziiert mit einer schlechten Prognose.

Schlussfolgerung

DNS-Sequenzvermehrungen auf 17 q sind nicht mit einer HER-2 Überexpression beim Adenokarzinom verbunden. Die Inaktivierung von Tumorsuppressor-Genen auf 18 q ist offenbar verantwortlich für die Tumorprogression sowohl des Adeno- als auch des Plattenepithelkarzinoms der Cervix uteri.

Abstract

Purpose

Cervical carcinomas are almost always squamous cell carcinomas, whereas adenocarcinomas are rare. There is evidence that specific genetic events are involved in initiation and progression of invasive cervical cancer. The genotype-phenotype correlations in cervical cancer are unclear.

Material and Methods

Comparative genomic hybridization was applied to screen for DNA copy number changes in 62 squamous cell carcinomas and 22 adenocarcinomas of clinical stage IB. Immunohistochemistry was performed in adenocarcinoma samples to determine the HER-2 expression (HercepTest^TM).

Results

In both cancer types, DNA sequence losses were most prevalent at chromosomes 4 q, Xq and 18 q. Losses were the most frequent alterations in squamous cell carcinoma, whereas DNA sequence gains of chromosome 17 q (54 %) represented the most frequent copy number alterations in cervical adenocarcinomas. HER-2 overexpression was detected in only two adenocarcinomas. The total number of DNA aberrations per tumor (P < 0.02), and the number of DNA sequence losses per tumor (P < 0.04) were associated with disease-specific survival in squamous cell carcinoma. 9 p deletions were significantly more frequent in squamous cell carcinomas with lymph node metastasis than in node negative tumors (P < 0.03). Losses of chromosome 11 p (P < 0.0001) and 18 q (P < 0.01) were associated with poor prognosis in squamous cell carcinomas without lymph node metastasis. In analogy to squamous cell carcinoma, DNA sequence losses of chromosome 18 q were significantly associated with poor prognosis in cervical adenocarcinoma (P < 0.01).

Conclusion

DNA sequence copy number gains on 17 q are not associated with HER-2 expression in adenocarcinomas. The inactivation of tumor suppressor genes on chromosome 18 q might be responsible for the progression of both cervical adenocarcinoma and squamous cell carcinoma.

Schlüsselwörter

Zervixkarzinom - Genomische Aberrationen - Chromosom 11 p - Chromosom 18 q - CGH

Key words

Cervical cancer - Genomic aberrations - Chromosome 11 p - Chromosome 18 q - CGH

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