THE PROBLEM OF SKIPPED GENERATION AND SUBCLINICAL DISEASE IN FAMILIALBREAST-OVARIAN CANCER

Background. The major gene for inherited breast ovarian cancer familie s shows high penetrance in female carriers. Daughters of living unaffe cted women in these families are supposed to have a low risk of cancer . Linkage analyses may be used to determine the probability that such families are linked to BRCA1 and, subsequently, to identify mutation c arriers in such families, Linkage analyses are dependent upon correct diagnoses of all family members. Methods. We report one breast-ovarian cancer family, prospectively observed, In which a mother and her daug hter contracted ovarian and breast cancer almost simultaneously. Linka ge analyses indicated that they both had the same BRCA1 mutation. The mother's sister had a possible premalignant lesion at oophorectomy. Di scussion. We discuss the problems raised by the pathological classific ation of possible premalignant lesions, that linkage analysts are sens itive to misclassification of diagnoses, and probability for skipped g eneration.