Allelic phasing of a mouse chromosome 11 deficiency influences p53 tumorigenicity

Most tumour suppressor genes (TSGs) have been found through linkage studies in cancer predisposed families where the mutations have a high penetrance, for example, the breast cancer genes BRCA1 and BRCA2. Loss of heterozygosity (LOH) analyses of sporadic breast tumours indicate that there are many other putative TSGs yet to be identified. One such locus is proximal to BRCA1 on human chromosome 17q21. In an attempt to isolate this putative TSG, we have assessed a portion of the orthologous region on mouse chromosome 11 for its tumorigenic potential using segmental haploidy in combination with a p53 mutation. Two populations of animals were studied, with the deleted region being either on the same (cis) or on the homologous chromosome (trans) to a targeted mutant p53 allele. The deficiency elevated the tumour susceptibility of p53 heterozygous mice and modified the tumour spectrum, but only when the deficiency was in trans with the p53 mutation. Even though the genotype of these mice is identical, allelic phasing affects both the tumour spectrum and progression.