To identify genetic determinants of human cancer, cancer families and genetic disorders predisposing to neoplasia are studied in an interdisciplinary approach to gain insights into human carcinogenesis. Haplotyping studies of our largest NF2 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 individuals, only 1 was shown to have an increased risk of having inherited the gene for NF2. The DNA from this same family was also an invaluable resource for the identification and cloning of the NF2 gene. 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. Great effort is now being focussed on determining the function of this tumor suppressor gene and defining mutations in individual families. Most NF2 patients will eventually become deaf or at least hearing impaired as a consequence of the growth of tumors or surgery to remove them. We documented that over 33% of our NF2 patients also had decreased visual acuity which was directly or indirectly related to 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 generate the following breast cancer incidence rates: overall age-adjusted rates in the cohort, rates by risk factor, and rates in persons with no risk factors. Using the same data, an analysis to determine whether the offspring of older mothers have an increased risk of breast cancer is planned for the near future.
