GENETIC EPIDEMIOLOGY OF EARLY-ONSET BREAST-CANCER

Risks for breast cancer when there is a family history of the disease are usually calculated using data from segregation analyses which favo ur a single dominant gene with high penetrance. There are, however, at least three loci known to be associated with familial breast cancer ( p53, BRCA1, and an as yet unpublished locus) and the frequencies and p enetrances of these genes are not likely to be the same. We have attem pted to address the problem of which genetic parameters should be used to calculate risks for different patterns of familial breast cancer. Data from 384 nuclear families ascertained through a proband selected for early onset breast cancer were subjected to complex segregation an alysis, correcting for ascertainment bias resulting from selection for severe phenotype. Age of onset of breast cancer, incorporated as seve rity, provides additional information to the segregation model over an d above that given by assigning liability classes on the basis of age at observation. The use of this additional parameter in the analysis i s described. There is fair agreement between estimates from this sampl e and previous predictions from consecutive probands and consultands. The differences suggest more than one rare dominant gene for susceptib ility to breast cancer, with different penetrances. Although refinemen ts of segregation analysis will help to delineate these different gene s, perfect resolution will require identification of the mutant allele s. Methods to estimate genetic parameters under genotype specific mort ality need to be developed. Meanwhile, we suggest that high and low es timates of penetrance be used in risk estimation for genetic counselli ng, and as a guide to candidates for entry into clinical trials of scr eening and chemoprevention in breast cancer.