Chromosomale DNA Gewinne und Verluste von Mikrometastasen aus Knochenmark und Lymphknoten bei Patienten mit operablen Ösophaguskarzinomen

Abstract

Background: The detection of micrometastatic tumor cells in bone marrow (BM) and lymph nodes (LN) is an independent and prognostic significant parameter for metastatic relapse and survival for patients with operable esophageal cancer. However, so far little is known about the biology of these cells. Therefore, we were interested in the genomic alterations of these tumor cells in esophageal carcinoma patients. Methods: We screened the BM and the LN of 51 patients with operable esophageal carcinoma (pT1 – 3, pN0 – 1, M0) for micrometastatic cancer cells. Twenty-eight epithelial cells identified by immunocytochemistry were isolated from BM and LN of 15 patients using micromanipulation. We globally amplified the genomic DNA of disseminated tumor cells using the Mse-adapter PCR method and performed comparative genomic hybridization (CGH) for the genome-wide screening of DNA gains and losses. Results: Chromosomal alterations were frequently detected in single micrometastatic tumor cells of patients with esophageal carcinoma. The mean number of chromosomal aberrations per cell was 6.9 and the observed chromosomal alterations were typical for tumors of this entity (deletions at 5q, 13q, 17p and amplifications at 8p, 17q). Interestingly, amplifications of the HER-2/neu locus on chromosome 17 were observed in 30% of the Single micrometastatic tumor cells. The gene product of HER-2/neu is currently tested as anti-cancer therapy. Conclusion: Our study provides a description of genomic alterations in minimal residual tumor cells detected in BM and LN of patients with operable esophageal carcinoma. The genomic data confirms the malignant tumorous origin of cells detected by cytokeratin antibodies in BM and EpCAM antibodies in LN. The altered chromosomal regions of the micrometastatic tumor cells may help to identify genes that regulate the growth of metastases. Moreover, genomic aberrations of disseminated tumor cells may become new prognostic markers and may help to discover new therapeutic targets for patients with esophageal cancer.