CANCER AND MORTALITY IN NEUROFIBROMATOSIS BY GENOTYPE

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Manifestations of neurofibromatosis 1 (NF1) vary widely even within families, and progression may be rapid or static, early or late, or erratic. Benign and malignant neoplasms occur to excess in persons with NF1, but estimated rates vary greatly. Prognostic information on survival is sparse. To address these issues and to begin relating them to specific mutations within the NF1 gene, we will follow up a nationwide cohort of patients with neurofibromatosis who were identified as far back as 1924. The three specific aims are: 1) to follow-up the national cohort of NF1 patients, last updated to June 1983, to extend each affected lineage to all subsequent descendants and to establish an ongoing mechanism of follow-up; 2) for all NF1 persons in the cohort, to determine mortality by specific causes of death and cancer incidence and to compare it with expected numbers, based on age-, year-, and sex-specific cancer rates from the Danish Cancer Registry; and 3) to determine the specific mutation within the NF1 gene in individuals in all 78 lineages to explore possible mutation-specific associations with mortality and cancer rates. Following the successful protocol from our study in the early 1980s, follow-up will take place by personal contact, clinical examinations, retrieval of church records, the Danish Central Population Register, death certificates, and hospital, pathology, and postmortem reports, as well as at the Danish Cancer Registry. Survival curves will be prepared by standard life-table methods; a person-years-at-risk analysis and relative risk calculation will assess a possible excess of cancers. Feasibility analysis of familial aggregation of cancer will be conducted. Blood for DNA and RNA will be collected on all subjects, and relevant spouses with or without NF1, and lymphocytes will be transformed by Epstein-Barr virus on older subjects and those with life-threatening disease. Duplicate specimen repositories will be established in Copenhagen and Pittsburgh. NF1 gene mutations will be sought by protein truncation assay, single-stranded conformation polymorphism gels, and automatic fluorescent sequencing. Patterns of mortality and cancer incidence will be compared by NF1 genotype. A longitudinal cohort will be established for subsequent studies.