The importance of genome architecture in cancer susceptibility: location, location, location.

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