Thus, a single pivotal genetic event, p53LOH, simultaneously provides three major evolutionary forces to drive cancer, (I) loss of residual WTp53 suppressor activity, including the repressive WTp53–HSF1 axis, (II) tumor-promoting HSF1 derepression, and (III) mutp53 stabilization enabling GOF activities. The gene discussed is HSF1; the disease is neoplasm.