Q: What happens that allows mutations in BRCA1 and BRCA2 to lead to cancer rather than causing cell death

DR. KING: That’s the other big puzzle in this field because these are genes involved in critical pathways. It was clear from very early knockout work that these genes are critical for development. The full knockouts were early embryonic lethals. So why do we ever see tumor development? It’s now clear that p53 may play a role in which alterations of p53 may modify the consequence of the knockout of BRCA1. It may well be the case that there is some small subset of cells, which even if the gene is knocked out, don’t die.

However, if another gene in either the DNA-repair pathway or the transcription-regulation complex is always lethal when knocked out, then it would never act as a gene for inherited predisposition because there would always be cellular death and no one would ever know that the mutation had occurred. So a tumor-suppressor gene that wishes to function, shall we say, teleologically as a gene with inherited predisposition has to tread a very fine line between being too good at killing the cell once there is a mutation and not having a genomic structure that allows somatic alteration to take place.