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Genome wide screening for tumour related rearrangements in mouse cancer models

Final Activity Report Summary - CANCER GENOME (Genome wide screening for tumour related rearrangements in mouse cancer models)

Background
Our project aims to perform one of the largest comprehensive analyses of the "cancer genome" in a cancer prone mouse model: irradiated BLOOM deficient mice. Loss of the DNA helicase BLOOM function has been described in human BLOOM syndrome and leads to a breakdown in the maintenance of genome integrity, in particular hyper-recombination and cancer predisposition. Mice deficient for this gene are cancer prone in a wide variety of different cell types including carcinomas, sarcomas and lymphomas.

Strategy
In order to produce a wide range of tumours of different types, a cohort of 1000 BLOOM deficient mice has been irradiated. Mice were sacrificed when terminally ill and tumours collected In order to identify gene/regions recurrently rearranged, tumour samples were subjected to a complete cytogenetic analysis, including high resolution array CGH (aCGH) and Multicolour FISH (M-FISH). Candidate regions/genes will be tested for their functional significance by single gene knockouts or chromosome engineering.

Results
-We have harvested thousands of tumour samples from different cell types.
-Thirty-too primary cultures, derivated from T lymphoma, have been analysed using high resolution aCGH and M-FISH. These 2 technologies allowed us to find already known candidates cancer region/genes (chromosome 11: Ikaros; Chromosome 15: c-Myc; chromosome 19: Pten), as well as a new region on chromosome 12, which was found to be involved often in translocation, and/or deleted. We were able to identify a 50 kb sub region around 108MB on chromosome 12, within a gene desert, which seemed particularly targeted. We are currently investigating the relevance if this region in cancer using chromosome engineering.
-This study is still ongoing and more tumour samples from different cell origins are currently being characterised.

Conclusions
The BLOOM deficient mice allowed us to harvest hundreds of tumour from different origins generating the tumour panel which is subjected to genetic analysis (aCGH and M-FISH). The strength of M-FISH is in defining translocations and marker chromosomes in complex karyotypes, whereas array CGH can reveal hidden deletions and amplifications. In combination, this promises a very powerful approach to cancer gene discovery.