The Importance of Genome Architecture in Cancer Susceptibility: Location,Location, Location

Tumorigenesis requires the interaction between different gene disruptions to convert anormal cell into a cancer cell. These gene disruptions can involve loss of expression ormisexpression of genes through genetic or epigenetic mutations. It is becoming clear that thesedisruptions are not isolated events in the genome, but are affected by genome architecture andthe syntenic relationship of alleles on chromosomes. A better understanding of the genetic andepigenetic changes in cancer is important for the rational design of new therapies. We haverecently shown that background-specific polymorphisms and loci under epigenetic regulationhave a strong effect on cancer susceptibility in a mouse model of astrocytoma. Although thesemice carry mutations in p53 and ras signaling pathways (through mutation of the rasGAPprotein, Nf1), the susceptibility to different tumor types depends strongly on epigeneticregulation and does not show simple Mendelian inheritance. Our results demonstrate theimportance of genome architecture and how tumorigenesis can be accelerated by concomitantloss or gain of multiple genes in a single chromosome rearrangement. Because genomearchitecture is very different between mice and humans, comparing patterns of genomicrearrangement in human cancer and mouse models may help distinguish causal genomic changesfrom correlative changes.