Service Communautaire d'Information sur la Recherche et le Développement - CORDIS


ISIS Résumé de rapport

Project ID: 322602
Financé au titre de: FP7-IDEAS-ERC
Pays: Germany

Mid-Term Report Summary - ISIS (Identification and targeting of somatic changes initiating sporadic cancers)

This project aims to generate a catalogue of cancer-initiating genetic changes in breast and lung cancer and melanoma. To do so we analyze the DNA of single disseminated cancer cells (DCCs) which we detect in the bone marrow and lymph nodes (LN) of cancer patients. We especially focus on a certain group of DCCs, the early arrested DCCs (EA-DCCs). These cells display few genetic lesions, because they apparently left the primary tumor very early after initiation and got arrested at the distant site, whereas primary tumor cells progressed genomically. We will use these cells to identify early cancer-initiating changes. DCCs that harbor many aberrations either left the primary tumor at a later time point or were able to aquire additional genetic lesions after dissemination. By comparing the genetic profiles of EA-DCCs, advanced DCCs and primary tumors we aim to unravel the sequence of genetic events in cancer development.

During the last years we generated a large sample bank of DCCs isolated from patients with breast and lung cancer and melanoma. To search for genetic losses and gains in single DCCs we developed a high resolution array CGH method for single cell analysis. We applied this method to identify DCCs with few and small genetic aberrations, the EA-DCCs. For breast and lung cancer as well as melanoma we identified EA-DCCs and started their characterization. For lung cancer and melanoma our DCC sample bank also includes DCCs from lymph nodes. Comparing lymph node and bone marrow DCCs of lung cancer patients revealed that arrested cells are mostly found in bone marrow whereas LN-DCC were able to progress. In melanoma we characterized EA-DCCs that presented morphologically as small cells but harbored genomic aberrations and rarely BRAF/NRAS mutations. In order to detect cancer-initiating genetic changes, we looked for recurrent genetic aberrations in DCCs, but noted pronounced genetic heterogeneity between cells of different patients as well as cells of the same patient. This was especially the case for DCCs of breast and lung cancer patients. Nevertheless, we identified some small regions that are shared among some DCCs of different patients. The high genetic heterogeneity suggests that the resolution needs to be increased further to identify shared alterations. We are now working on a protocol for single cell error free sequencing to be able to detect somatic single nucleotide polymorphisms in EA-DCCs.

For functional analysis of the detected early and shared genetic changes we aim to establish patient-derived cell lines. So far we succeeded in the generation of DCC-derived melanoma cell lines, and established patient models from matched primary tumors that will be used in the genetic screens planned for the second funding period.

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