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      Growth Hormone-Secreting Tumors: Genetic Aspects and Data from Animal Models

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          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 α regulatory subunit (R1α) 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.

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          Most cited references 68

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          Molecular genetic studies of familial cancer syndromes identified and defined the recessive nature of tumor suppressor genes and resolved the paradox of why tumors arising in such families exhibited an autosomally dominant pattern of inheritance. Subsequent characterization of tumor suppressor proteins revealed their widespread involvement in sporadic cancers and pinpointed key mechanisms that protect animals against tumor development. We now recognize that tumor suppressor genes regulate diverse cellular activities, including cell cycle checkpoint responses, detection and repair of DNA damage, protein ubiquitination and degradation, mitogenic signaling, cell specification, differentiation and migration, and tumor angiogenesis. Their study has become a centerpiece of contemporary cancer research.
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            Most cancers have many chromosomal abnormalities, both in number and in structure, whereas some show only a single aberration. In the era before molecular biology, cancer researchers, studying both human and animal cancers, proposed that a small number of events was needed for carcinogenesis. Evidence from the recent molecular era also indicates that cancers can arise from small numbers of events that affect common cell birth and death processes.
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              Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.

              Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.

                Author and article information

                S. Karger AG
                October 2006
                16 October 2006
                : 83
                : 3-4
                : 166-178
                Division of Endocrinology and Metabolism, Hippokrateion General Hospital, Athens, Greece
                95525 Neuroendocrinology 2006;83:166–178
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 94, Pages: 13


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