Molecular Genetics of Adrenocortical Tumors and Related

Child Health And Human Development

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Abstract

Summary of Work: The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are hereditary and associated with multiple tumors and abnormalities in other endocrine glands (i.e. the pituitary gland). Our laboratory has studied families with Carney complex (CNC) (also known as the complex of myxomas, spotty skin pigmentation, endocrine overactivity and schwannomas) and related syndromes and has identified two loci harboring genes for CNC on chromosomes 2 (2p16) and 17 (17q22-24). Through clinical investigations, better diagnostic procedures and treatment means for these patients are tested. Through genetic linkage analysis and other molecular genetic and cytogenetic techniques, the participation of the two genomic loci on chromosomes 2 and 17 in the expression of the disease is being investigated. A comprehensive genetic and physical map of the 2p16 chromosomal region was constructed for the cloning of the CNC-causing gene from that area. Studies in cultured primary tumor cell lines (established from our patients) identified a region of amplification in the center of this map. However, other tumors show loss-of-heterozygosity (LOH) of that region. From the 17q22-24 locus, LOH studies led to the identification of the PRKAR1A gene as the gene responsible for CNC in approximately 40% of the cases of the disease. PRKAR1A is a novel tumor suppressor gene; in collaboration with other laboratories at the NIH, the functional consequences of PRKAR1A mutations are being investigated in cell lines; more recently, animal models with transgenic expression of mutant PRKAR1A are being created. In collaboration with Mayo Clinic, the genetic defects in patients with CNC-related syndromes (i.e., Peutz-Jeghers syndrome) are also being identified. A genome-wide screen for the identification of gene(s) responsible for inherited adrenocortical aldosteronomas (familial hyperaldosteronism type II - FH-II) was also recently completed in our laboratory, identifying a locus for FH-II on 7p22. Additional work is being done collaboratively on the genetics of other endocrine tumors, including childhood adrenocortical cancer and pituitary tumors.