Genetics of adrenocortical tumors: Carney complex

Adrenal cancer is a rare neoplasm; however, up to 1 in 1500 adrenal inciden talomas may hide a carcinoma, which, if diagnosed late or left untreated, i s associated with significant morbidity and mortality. Despite extensive in vestigation of the molecular mechanisms involved in adrenal carcinogenesis and significant improvements in diagnostic imaging, efforts to cure advance d adrenal cancer remain largely unsuccessful. Thus, the investigation of th e genetics of adrenocortical cancer by the candidate or positional cloning gene approach is essential in the development of new therapies for this dis ease. We propose that adrenocortical tumorigenesis follows a pattern simila r to that in other organs : As the pathology of the adrenocortical tumor in creases towards malignancy, the genetic changes that are observed also incr ease. Known genetic associations, like TP53 gene changes, occur during the latest stages of adrenocortical tumorigenesis. Thus, it is essential to stu dy the relatively few genes that are affected at the beginning of this proc ess, at the stages of benign tumorigenesis in the cortex. We have studied p rimary pigmented adrenocortical disease (PPNAD), a benign, bilateral, adren ocortical hyperplasia, which either in its isolated form or as part of Carn ey complex (CNC), is inherited in an autosomal dominant manner and, therefo re, the gene(s) responsible for this disorder could be identified by positi onal cloning approaches. Indeed, we have identified two genetic loci harbor ing genes for PPNAD and/or CNC on chromosomal loci 2p16 and 17q22-24. The c hromosome 17 gene, PRKAR1A, was recently cloned and the identification of o ther responsible genes is currently under way in our, and collaborating lab oratories. The present report reviews the genetics of adrenocortical cancer first, followed by what is known today about the genetics of PPNAD and/or CNC.