Heritability of breast cancer and its role in pre-menopausal cases.

The causes for the pre-menopausal incidence peak in breast cancer are still controversial. Other cancers also show an early incidence peak. Since the mammary tissue only starts to develop in puberty, the pre-menopausal incidence peak for breast cancer is comparable to the 'juvenile' peak in other cancers (retina, kidney). The four-mutation model for oncogenesis can explain pre-menopausal breast cancer. The model suggests that malignant transformation of a cell is due to four specific oncogenic mutations. These specific mutations accumulate during the proliferation of somatic cells. According to the model, one inherited oncogenic mutation can cause hereditary cancer. In this case only three additional specific mutations have to be accumulated during somatic cell proliferation. Epidemiological data and mathematical calculations indicate that in this case tumors occur early in life. Thus, the four-mutation model for oncogenesis predicts that the impact of heritability in pre-menopausal breast cancer is more significant than is generally believed. At this point, molecular biological studies are needed, to identify the involved specific mutations. Other implications of the model are an increased incidence of second primary tumors and an increased sensitivity for mutagenic factors in these patients.