Genetic analysis of susceptibility to endometrial adenocarcinoma in the BDII rat model.

Most cancers are genetically complex and heterogeneous, a serious obstacle to identifying specific genes underlying the disease. If inbred animal models are used, then both the genetic constitution and environmental influences can be carefully controlled. Females of the BDII inbred rat strain are genetically predisposed to endometrial cancer; more than 90% of virgin BDII females will develop endometrial adenocarcinoma (EAC) during their life span. BDII females were crossed to males from inbred strains with low EAC incidence (SPRD or BN). When F(1) males were backcrossed to BDII females to generate N(1) populations of offspring, about one fourth of the female progeny developed EAC. With transmission disequilibrium test analysis, significant association was detected in three chromosomal regions (on RNO1, RNO11, and RNO17) in the SPRD crosses and in the short arm of RNO20 in the BN crosses. It appears that several susceptibility genes with minor but cooperating effects are responsible for the susceptibility. Furthermore, it seems clear from the interstrain crosses not only that the onset of tumors depends on the presence of susceptibility alleles from the EAC-prone BDII strain, but also that tumor development is affected by the contribution of a genetic component derived from the nonsusceptible strains.