Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues in collaboration with an international consortium. Other studies within the consortium include a determination of the penetrance of melanoma in families with CDKN2A mutations. Comparison of penetrance in high-risk and low-risk countries will be made. An international collaborative study determined the origin of the most common CDKN2A mutation Gly101Trp. Twenty families from France, Italy, and the United States were haplotyped to determine that the Gly101trp mutation probably resulted from a single ancestor approximately 97 generations ago. In a consortium study, 48 families at high risk of melanoma were screened for germline mutations in a candidate susceptibility gene p19 INK4D. Although no mutations were found, given its chromosomal location at a translocation site, p19 INK4D may be a rare susceptibility gene. Clinical evaluation of 20 Italian melanoma-prone families with predominantly dark complexions showed that clinical features were similar to those observed in fair skinned populations. There was a strong correlation between dysplastic nevi and melanoma in these families. Molecular examination of these 20 melanoma-prone families revealed no coding region CDKN2A or CDK4 mutations, suggesting that other genes are likely involved in this lower risk population. Review of radiologic and clinical data on spinal tumors in members of NF2 families suggested that intramedullary tumors were associated with less morbidity than nerve sheath tumors or meningiomas. NF2 genotype influenced spinal tumor phenotype: a higher percentage of patients with nonsense or frameshift mutations had intramedullary tumors as well as higher mean numbers of these and nerve sheath tumors than patients with other types of mutations. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include individuals with chordoma identified through the SEER system. Three new families have been identified and are being evaluated. Attempts to localize the gene continue. The study of chronic lymphocytic leukemia was also expanded by use of a newsletter and a website. A genome-wide search for susceptibility genes is in progress. Other laboratory investigations include characterization of protein expression of candidate loci, cell surface marker analysis, characterization of telomerase activity in tumor cells, and analysis of expressed immunoglobulin heavy chains. A new study of Waldenstrom's macroglobulinemia was also initiated.
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