Familial versus sporadic breast cancer.

BACKGROUND: Studies comparing patients with familial and sporadic breast cancer have indicated that a family history of the disease can increase a woman's risk for having the disease twofold to threefold and that patients with familial breast cancer have a younger age at diagnosis and have a higher frequency of bilateral disease than those with sporadic breast cancer. Also, at least four types of breast cancers have been shown to be inherited. These findings led to the hypothesis that familial and sporadic breast cancer are the consequence of two biologically distinct mechanisms.
METHODS: A two-step mutation model proposed by Knudson in 1971 provides a link between the molecular mechanisms underlying familial and sporadic breast cancer. According to this model, both cancers involve the same genomic change in homologous chromosomes. The only difference is that the first mutation is inherited and the second is somatic in familial cancer, whereas in sporadic cancer both mutations are somatic. Mutation is used in a broad sense and refers to either a point mutation at a specific locus or the loss of a locus by deletion or nondysfunction.
RESULTS: This model has been shown to apply to several childhood and adult cancers, including breast cancer. Based on this model, patients with familial breast cancer will have their disease earlier in life and will have more bilateral cancer than patients with sporadic breast cancer. Moreover, the two types of patients should show no differences in clinicopathologic characteristics because both types involve the same genomic change and the pathogenesis of both types should be the same, thus arguing against the early hypothesis that patients with familial and sporadic breast cancer are the consequence of biologically distinct mechanisms.
CONCLUSIONS: Breast cancer appears to involve the cumulative effect of several genetic lesions involving the activation of oncogenes and the inactivation of tumor-suppressor genes. Which genes are involved specifically as causative factors of breast cancer (the inherited gene or genes) and which are important somatically in its continued development and progression (oncogenes and tumor-suppressor genes) requires additional study.