MUTATIONS IN ADRENOCORTICAL TUMORS

Silent and incidentally detected adrenocortical neoplasms are the most frequent abnormality of the adrenal cortex. The prevalence of these l esions in the general population is around 1%, increases with age and reaches 6% in the seventh decade of life. Primary adrenocortical carci noma, on the other hand, a highly malignant tumor, is rare with an inc idence of 1.7 cases per million per year. Recent progress has been ach ieved in the understanding of adrenocortical tumorigenesis by mapping and identification of genes responsible for hereditary tumor syndromes like the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Carney co mplex and the Multiple Endocrine Neoplasia Type I. Investigation of th e clonal composition of adrenal tumors demonstrates that adrenal carci nomas are generally monoclonal, whereas adrenal adenoma may be polyclo nal in approximately 25% of cases. These adenomas may have a multicell ular origin under the putative action of extra-adrenal and local growt h factors. Oncogenes and tumor suppressor genes involved,in adrenal ca rcinomas include mutations in the p53 tumor suppressor gene and rearra ngements of the chromosomal locus 11 p15.5 associated with ICF II hype rexpression. Constitutive activation of the ACTH receptor-G protein-cA MP signal cascade does not play a role in adrenal tumor formation. Con versely, deletions of the ACTH receptor gene have been recently found in undifferentiated adenomas and in aggressive adrenocortical carcinom as. This indicates that the signaling pathways responsible for adrenoc ortical tumor formation are different from that of other endocrine neo plasms like pituitary and thyroid adenomas.