To identify genetic determinants of human cancer, families with cancer or genetic disorders predisposing to neoplasia are studied in an interdisciplinary approach to gain insights into human carcinogenesis. DNA from our largest NF2 family has been an invaluable resource for the identification and cloning of the NF2 gene by two different laboratories. A large deletion in the candidate gene for NF2 was present in 5 affected family members but not in 11 unaffected relatives. The co-segregation of the deletion and the disease phenotype in this family confirmed that the deleted gene was the gene for NF2. Haplotyping studies of the same family using DNA markers flanking the NF2 gene have demonstrated the utility of this approach in estimating the risk of inheriting the gene for NF2 in asymptomatic individuals with an a priori 50% risk for this condition. Out of 20 tested at-risk individuals, only 1 was shown to have an increased risk of having inherited the gene for NF2. Analysis of the clinical findings in our patients supports the proposal of two subtypes: in the mild subtype vestibular, schwannomas are the main central nervous system manifestation; while in the intermediate-severe form, additional brain and spinal tumors are common. We will look for correlations between type of NF2 mutation and these subtypes when mutations studies on our patients are completed. We documented that over 37% of our NF2 patients have peripheral cortical lens opacities. This is the second type of lens opacity that we have found to be associated with NF2. Thus, an ophthalmologic evaluation should be part of the routine medical care of every NF2 patient. National Health and Nutrition Examination Survey (NHANES I) follow-up data are being used to estimate the impact of a first degree family history of breast cancer, nulliparity and age at first birth combined, and age at menopause on breast cancer incidence in the US population.
