Article
Clinical relevance and molecular characteristics of disseminated cancer cells in patients with non-small-cell lung cancer
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Published: | October 14, 2013 |
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Objective: Despite complete resection of the primary tumor approximately 40% of all non-small-cell lung cancer (NSCLC) patients relapse within 24 months after primary surgery. Early dissemination of cancer cells may be a major reason for this observation. Detailed molecular characterization of disseminated cancer cells (DCC) is, therefore, critical for understanding the processes regulating metastatic cancer spread in lung cancer. In this study, we determined the clinical relevance of lymphatically and hematogenously DCC in a cohort of 119 non-metastatic (M0) non-small-cell lung cancer patients. Furthermore, we performed whole-genome screens of isolated single DCC aiming to identify frequently altered loci with possible clinical or prognostic implications.
Methods: DCC in lymph nodes (LN) and bone marrow (BM) were detected using antibodies against the epithelial cell adhesion molecule (EpCAM, CD 326) or cytokeratins 8/18/19, respectively. Presence of DCC was correlated with overall survival using Kaplan-Meier and Cox-regression analyses. Individual single cells were subjected to single cell metaphase genomic hybridization (CGH) or high-resolution array CGH.
Results: Survival analysis revealed that presence of DCC in lymph node and bone marrow at the time of surgery is associated with significant shorter survival time of non-small-cell lung cancer patients. DCC from bone marrow and lymph nodes showed highly divergent profiles of genomic aberrations. Frequent gain of chromosome 7q31, a region comprising MET, was frequently detected in DCC isolated from lymph nodes, while BM DCC displayed fewer and less typical aberrations. We identified very few aberrations that were shared between LN and BM DCC.
Conclusion: The presence of DCC in bone marrow or lymph nodes represents a strong prognostic factor for relapse and poor overall survival. The comparison of early DCC in BM versus LN may uncover changes that are shared at the time of dissemination. Such changes may reveal putative therapeutic targets at the stem of the phylogenetic tree of an individual cancer.