Towards a genetic-based classification of human lung cancer

Lung cancer is a highly aggressive neoplasm which is reflected by a multitu de of genetic aberrations being detectable on the chromosomal and molecular level. In order to understand this seemingly genetic chaos, we performed C omparative Genomic Hybridisation (CGH) in a large collective of human lung carcinomas investigating different tumor entities as well as multiple indiv idual tumour specimens of single patients. Despite the considerable genetic instability being reflected by the well known morphological heterogeneity of lung cancer the comparison of different tumour groups using custom made computer software revealed recurrent aberration patterns and highlighted ch romosomal imbalances that were significantly associated with morphological histotypes and biological phenotypes. Specifically we identified imbalances in NSCLC being associated with metastasis formation which are typically pr esent in SCLC thus explaining why the latter is such an aggressive neoplasm characterized by widespread tumor dissemination. Based on the genetic data a new model for the development of SCLC is presented, It suggests that SCL C evolving from the same stem cell as NSCLC should be differentiated into p rimary and secondary tumors. Primary SCLC corresponding to the classical ty pe evolved directly from an epithelial precursor cell. In contrast, seconda ry SCLC correlating with the combined SCLC develops via an NSCLC intermedia te. In addition, we established libraries of differentially expressed genes from different human lung cancer types to identify new candidate genes for several of the chromosomal subregions identified by CGH. In this review, w e summarise the status of our results aiming at a refined classification of lung cancer based on the pattern of genetic aberrations.