Study of preneoplastic genetic diseases with a high risk of cancer may help detect environmental and genetic influences in carcinogenesis, especially when appropriate laboratory assays are used. Neurofibromatosis, an autosomal dominant disorder with a predisposition to cancer, received emphasis. Results on 19 families lowered the likelihood of linkage to GC, a chromosome 4 marker, from a lod score of 0.9 in first reports to 0.6. Assays of DNA restriction fragment length polymorphisms confirmed a lower likelihood of mapping to chromosome 4 and failed to suggest an alternative. Prophase karyotypes in 14 affected patients were normal. Forty-year follow-up of 212 neurofibromatosis patients in Denmark permitted life-table analysis: survival was worst for females who were the original probands, slightly better in male probands, and only slightly less than rates expected in the general population in affected relatives. The relative risk for malignant neoplasms was 4.0 in probands, but only marginally elevated in relatives. This ascertainment bias was similarly demonstrated by recognizing """"""""atypical features"""""""" in family members of a proband with Sotos' syndrome (cerebral gigantism), which enlarged the spectrum of the syndrome. Similar multidisciplinary approaches to two other preneoplastic syndromes revealed, in the nevoid basal cell carcinoma syndrome, a lod score of 1.2 to amylase 1 on chromosome 1p, and an association with auditory defects; in the dysplastic nevus syndrome, a possible excess of chromosome breaks. The day-night differences in plasma melatonin levels, unusually small in women with estrogen receptor-positive breast cancer, were normal in women at very high risk of breast cancer because of their family history. Cytogenetic abnormalities associated with human cancer were summarized in a figure emphasizing the genes assigned to specific chromosomes, including the newly described human oncogenes.
