Fig. 1

Mechanism leading to the acquisition of increased genomic instability in normal cells from persons with or without a highly penetrant germline mutation conferring enhanced risk for cancer (e.g., a BRCA1 mutation). A normal cell can acquire enhanced genomic instability (a mutator phenotype, one of the first steps in tumorigenesis) through a one-step (dominant mutations) or a two-step (recessive mutations) mechanism. According to the classical TSG-based model (a), normal cells from all individuals present the same genomic stability. Individuals without a cancer predisposing mutation (wt/wt) have a low probability to acquire a mutator phenotype through the accumulation of specific mutations (red arrows). Normal cells from a high cancer risk person (wt/BRCA1mut) can acquire increased genomic instability in the same way as wt/wt cells, but preferentially by inactivation of the remaining wild-type BRCA1 allele (the thickness of the arrows reflects the relative probability at which the event will occur). In the alternative model (b), normal cells from a person with a cancer predisposing germline mutation would already manifest a slightly increased genomic instability resulting in the faster accumulation of somatic mutations. This increased genomic instability would be the primary cause for a cancer predisposed cell to acquire a mutator phenotype. In cells with a highly penetrant germline mutation, the mutator phenotype is preferentially acquired through inactivation of the remaining wild-type allele. Without the increased genomic instability associated to this germline mutation in normal cells, this “second hit” will most probably not occur