DELETION OF THE ADRENOCORTICOTROPIN RECEPTOR GENE IN HUMAN ADRENOCORTICAL TUMORS - IMPLICATIONS FOR TUMORIGENESIS

Constitutive activating mutations of G protein-coupled receptors, such as that of TSH, have been implicated in the tumorigenesis of human en docrine neoplasms, such as thyroid adenomas. In a previous study we re ported that constitutive activating point mutations of the ACTH recept or (ACTH-R) gene, a member of the G protein-coupled receptor superfami ly, were not present in hormone-secreting and nonsecretory adrenocorti cal neoplasms. In this study, we investigated whether allelic loss of the ACTH-R gene is present in sporadic adrenal tumors. We identified a PstI polymorphism in the promoter region 3 kilobases upstream of the coding region of the ACTH-R gene. The rate of heterozygosity for this polymorphism in 99 unrelated Caucasian individuals was 53.5%. Using th is polymorphism, we analyzed loss of heterozygosity (LOH) of the ACTH- R gene in 20 informative cases with beni,sn and malignant adrenocortic al tumors. Of 16 patients with benign lesions, LOH was present in 1 on cocytic nonfunctional adenoma, but not in 15 hyperfunctioning adenomas . Of 4 informative patients with adrenocortical carcinomas, LOH was pr esent in 2 cases. Both patients had advanced tumor stages and showed a more rapid course than carcinoma patients without LOH. Analysis of th e flanking region of the ACTH-R using the polymorphic microsatellite m arker D18S37 and D18S40 showed that this deletion was confined to the ACTH-R gene. Northern blot experiments demonstrated reduced expression of ACTH-R messenger ribonucleic acid in the tumors with LOH of the AC TH-R gene, suggesting functional significance of this finding at the t ranscriptional level. We conclude that LOH of the ACTH-R gene is possi bly involved in adrenal tumorigenesis, contributing to cellular dediff erentiation in adenomas and carcinomas.