Growth hormone-secreting tumors: genetic aspects and data from animal models

Hereditary cases of growth hormone (GH)-secreting tumors have been classified into three clinical entities: the multiple endocrine neoplasia type 1 (MEN1) syndrome, the Carney complex (CNC) and the isolated familial somatotropinomas (IFS). The genomic defects associated with MEN1 are all linked to various mutations of the MEN1 gene, which is located at chromosome 11q13 and codes for menin, a nuclear protein expressed in multiple tissues. Inactivation of the MEN1 gene appears to be only rarely associated with sporadic pituitary tumor development. A CNC-associated gene, the type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PRKAR1A), is located at 17q23-24. A second CNC candidate gene is located at chromosome 2p15-16, with characteristics of inheritance consistent with an oncogene; however, this gene has not been identified yet. PRKAR1A mutations are infrequently associated with sporadic GH-secreting adenomas. A candidate IFS gene is located at 11q13, in proximity to the MEN1 gene, at a locus narrowed down to a 2.21-Mb area, with approximately 50 genes, that does not appear to include the MEN1 gene. Apart from the linkage of IFS to 11q13, a possible linkage to 2p16 has also been raised, although data are still inconclusive. This manuscript reviews genetic aspects of hereditary GH-secreting tumors, data from animal models resulting from the inactivation of the MEN1 and PRKAR1A tumor suppressor genes and available in vitro data regarding possible functions of menin, the product of the MEN1 gene.