The general objective of this project is to gain expertise in molecular genetics and acquire the laboratory skills necessary for applying genetic strategies to the understanding, diagnosis and possible treatment of endocrine tumors. Multiple endocrine neoplasia type 2(MEN 2), a rare cancer syndrome genetically transmitted in an autosomal dominant pattern with age-dependent biochemical and clinical penetrance, is characterized by the concurrence of medullary thyroid carcinoma as the index lesion with variable expression of multiple neural crest abnormalities. The MEN 2 predisposition locus has been assigned to the pericentromeric region of chromosome 10 by linkage analysis (1,2,3) with evidence favoring genetic homogeneity in reported kindreds (4). Development of existing markers has been achieved primarily using the traditional and less informative method of restriction fragment length polymorphism (RFLP) analysis. Moreover, the gene altered in the MEN 2 syndrome has not been identified or its product characterized. The objectives of this study are fourfold: 1) to generate additional markers in the pericentromeric region of chromosome 10 using microsatellite polymorphisms, a more efficient and informative approach than RFLP analysis; 2) to confirm co- inheritance of the DNA markers identified to the MEN 2 gene and test their value in early diagnosis; 3) to generate an abundance of sequence- tagged sites (STSs) from the subregion encompassing the MEN 2 locus for further isolation of yeast artificial chromosomes (YAC) clones; and 4) to refine the genomic structure of the pericentromeric area of chromosome 10 by contig assembly with YAC clones. Accomplishment of these aims will be possible by the educational and laboratory resources made available to me through the Human Genome Center at the University of Michigan under the sponsorship of Dr. Francis Collins.
