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The role of loss-of-heterozygosity in cancer development and progression

Final Report Summary - DELCANCER (The role of loss-of-heterozygosity in cancer development and progression)

One-fourth of a typical breast cancer genome is affected by chromosome arm deletions. The concomitant loss of multiple genes creates vulnerabilities that are impossible to reveal through the study of individual genes. By genetically engineering human cells to carry large-scale deletions in the absence of ancillary genetic abnormalities, we generated clinically relevant models of disease-associated chromosomal deletion. Comprehensive analysis of the generated models revealed that large-scale deletions disturb multiple signaling pathways and produce phenotypes distinct from those arising through loss of a single gene and should be considered as distinct mutational events. Chromosome engineering also permits the generation of novel genetic configurations for the functional analysis of the genome. In particular, we revealed that chromosomal deletions trigger changes in physical long-range chromosomal interactions that affect expression pattern of specific chromatin hubs. Finally, the generated isogenic cells represent a useful platform to identify drugs that selectively kill tumor cells harboring a particular chromosomal abnormality. Our results demonstrate that experimental models mimicking cancer-associated chromosomal abnormalities will improve our understanding of human cancer. Moreover, the generation of human cell models harboring targeted chromosomal deletions can also provide essential reagents for maximizing the efficiency of large-scale functional genomics efforts and accelerate the functional annotation of the human cancer genome.