Final Activity Report Summary - LUNG MICROMET (Identification of molecular signatures determining early metastatic spread of lung carcinomas in women)
Despite some improvements in treatment, mortality among lung cancer patients still remains extremely high, with the five-year survival rate being currently only around 15 %. In most cases, mortality is linked to metastasis, the spread of cancer cells to regional lymph nodes (LN) and distant organs such as liver, brain or the skeleton. Notably, approximately 30 to 40 % of patients with non-small cell lung cancer (NSCLC) without clinical signs of either LN or distant metastasis at the time of the primary surgery have a relapse within 24 months. Disseminated tumour cells (DTC) or micrometastases may thus have been present at the time of resection of the primary tumour, but undetectable by current clinical processes. Therefore, understanding the very early molecular processes in the metastatic cascade is of crucial interest. No study has so far, to our knowledge, linked the presence of specific molecular changes with early lung cancer dissemination.
In this EU- Marie Curie project, the aim was to assess whether the invasiveness and early metastatic spread of primary pulmonary tumours were associated with specific molecular patterns. As a marker for early spread we investigated disseminated tumour cells (DTC) in bone marrow (BM).
Through using a high-resolution comparative genomic hybridisation (CGH) and expression arrays we performed genome wide DNA aberration and expression profiling of primary lung tumours. The genomic aberration profiles of the tumours from patients with and without DTC in the BM were then compared in order to find specific molecular changes associated with DTC status. We could find, for the first time, tumour-specific genetic signatures involved in early hematogeneous dissemination of lung tumours. We also identified five chromosomal regions differentiating BM-negative from BM-positive patients. Copy number changes on chromosome 4q were the most prominent finding, containing the highest number of differentially expressed genes. In BM positive patients 4q was mostly lost, whereas some gains could be found among BM negative patients. Interestingly, loss of 4q was also associated with formation of distant metastases. The same loss was also found to be common in brain metastases from both small and non-small-cell lung cancer patients.
In conclusion, to our knowledge, this is the first study identifying tumour-specific genomic signatures involved in the early hematogeneous dissemination of lung tumour cells. Furthermore, we could show that loss of 4q might also be an important determinant for outgrowth of distant metastases. It will thus be an important goal in future studies to identify the target gene within 4q and explore its functional relevance.
In this EU- Marie Curie project, the aim was to assess whether the invasiveness and early metastatic spread of primary pulmonary tumours were associated with specific molecular patterns. As a marker for early spread we investigated disseminated tumour cells (DTC) in bone marrow (BM).
Through using a high-resolution comparative genomic hybridisation (CGH) and expression arrays we performed genome wide DNA aberration and expression profiling of primary lung tumours. The genomic aberration profiles of the tumours from patients with and without DTC in the BM were then compared in order to find specific molecular changes associated with DTC status. We could find, for the first time, tumour-specific genetic signatures involved in early hematogeneous dissemination of lung tumours. We also identified five chromosomal regions differentiating BM-negative from BM-positive patients. Copy number changes on chromosome 4q were the most prominent finding, containing the highest number of differentially expressed genes. In BM positive patients 4q was mostly lost, whereas some gains could be found among BM negative patients. Interestingly, loss of 4q was also associated with formation of distant metastases. The same loss was also found to be common in brain metastases from both small and non-small-cell lung cancer patients.
In conclusion, to our knowledge, this is the first study identifying tumour-specific genomic signatures involved in the early hematogeneous dissemination of lung tumour cells. Furthermore, we could show that loss of 4q might also be an important determinant for outgrowth of distant metastases. It will thus be an important goal in future studies to identify the target gene within 4q and explore its functional relevance.