Trends in Endocrinology & Metabolism
Genetics of adrenocortical tumors: gatekeepers, landscapers and conductors in symphony
Section snippets
Genomic and molecular cytogenetic studies
Comparative genomic hybridization (CGH) indicates genetic aberrations in adrenocortical tumors from adult 5, 6 and pediatric [7] patients, with several differences that might correlate with the clinical differences associated with tumors that form at a young age. The most common genetic aberrations in carcinomas are gains of chromosomes 4 and 5, and losses of chromosomes 11 and 17 [5]. The loss of 17q was observed frequently in a recent CGH analysis of adrenal tumors from several age groups,
The case for inhibin
Of the factors studied in adrenocortical tumors, the involvement of inhibin-A in human tumorigenesis remains a mystery. In rodents, inhibin plays a role in tumor formation [17]. Homozygous knockout Inha−/− mice develop gonadal tumors at 4–5 weeks of age and die at 12 weeks. Gonadectomy postpones the wasting syndrome, the development of adrenal tumors (21 weeks) and death (33–36 weeks) 18, 19. In another transgenic-mouse model that expresses a 6 kb fragment of the Inha promoter fused with the
Low-penetrance TP53 mutations
It has been suggested that low-penetrance mutations of established tumor-suppressor genes underlie adrenocortical tumors in at least some patients [25]. Indeed, a germline mutation in TP53 (R337H) was described in 35 out of 36 Brazilian children with either adenomas or carcinomas but no other identifiable clinical syndromes (i.e. Li–Fraumeni and Beckwith–Wiedemann syndrome) [26]. The same mutation was identified subsequently by Latronico et al. in other children and adult Brazilian patients
PRKAR1A: a gene for inherited and sporadic Cushing's syndrome
Various components of the cAMP-dependent protein kinase A (PKA) signaling pathway, including the genes that encode the corticotropin (ACTH) receptor (MC2R) and the Gsa subunit (GNAS1) are also implicated in adrenocortical tumorigenesis [30]. Recently, the gene that encodes the PKA type I-α regulatory subunit (RIα), PRKAR1A, was found to be responsible for most cases of a relatively rare form of bilateral adrenocortical hyperplasia called primary pigmented nodular adrenocortical disease (PPNAD),
Macronodular hyperplasia: ectopic receptors and other genes
In 1964, Kirschner et al. [44] described a 40-year-old woman with long-standing Cushing's syndrome. Although her disease was not ACTH-dependent, testing showed hyper-responsiveness to ACTH and that glucocorticoid production was not suppressed by the administration of dexamethasone. The patient underwent bilateral adrenalectomy; her adrenal glands had multiple nodules and a combined weight of 94 g (the weight of adrenal glands is usually 8–12 g). There have been >200 patients with macronodular
Immunohistochemical and other molecular markers
Cytokines, growth factors, and their receptors, which can be expressed eutopically or ectopically in adrenocortical tissue, have been implicated recently in carcinogenesis [60]. Expression of major histocompatibility complex class-II antigens in adrenocortical tissue correlates with adrenocortical cell differentiation [61]. The expression of both transforming growth factor α (TGFα) and epidermal growth factor receptor [62] is elevated markedly in carcinomas (unlike adenomas), and synaptophysin
Other ‘syndromic’ genes
Could other genes that cause human genetic-tumor syndromes also be involved in the pathogenesis of adrenocortical tumors in addition to TP53 and IGF2? I have already mentioned menin, PRKAR1A, GNAS1 and neurofibromin. Patients with familial polyposis coli and germline mutations of the APC gene also get, mostly nonfunctional, adrenal tumors 65, 66; however, APC has not been studied in sporadic adrenal tumors. Patients with the Carney triad (which consists of gastric stromal tumors, pulmonary
A model for adrenocortical tumorigenesis: ‘conductor’ genes
The studies reviewed here support the notion that adrenocortical tumorigenesis, like oncogenesis in other tissues [69], is a multi-step process (Fig. 1). Every step in this process is associated with an increasing number of genetic changes, as shown by CGH 5, 6, 7, 8. Inactivating mutations of TP53 and either chromosomal deletions or gains are frequent in cancers and large adenomas. Although these changes are either rare or nonexistent in hyperplasias and small adenomas, in some cases, genetic
Concluding remarks
This is an exciting time for clinicians and research scientists interested in primary tumors of the adrenal gland. Microarray technology and the identification of genes and molecular pathways that are specific to adrenocortical tumorigenesis are the ways of the immediate future. As the molecular basis of adrenocortical tumors becomes better understood, clinicians now faced with an increasing incidence of these lesions [82] will be able to offer better therapies to their patients. And,
Acknowledgements
I thank Caroline Sandrini (Santa Catarina, Brazil) for Fig. 2.
References (82)
Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chromosome 17 is an early event in adrenocortical tumorigenesis
Am. J. Pathol.
(1999)Analysis of numerical chromosomal aberrations in adrenal cortical neoplasms by fluorescence in situ hybridization
J. Urol.
(2002)Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors
Am. J. Hum. Genet.
(1999)- et al.
The regulatory subunit of cAMP-dependent protein kinase as a target for chemotherapy of cancer and other cellular dysfunctional-related diseases
Pharmacol. Ther.
(1993) Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and/or primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD
Am. J. Hum. Genet.
(2002)Cushing's syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome
J. Pediatr.
(1999)Adrenocortical tumor in a patient with familial adenomatous polyposis: a case asociated with a complete inactivating mutation of the APC gene and unusual histologic features
Hum. Pathol.
(1998)Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence
Mayo Clin. Proc.
(1999)- et al.
Lessons from hereditary colorectal cancer
Cell
(1996) - et al.
Thinking beyond the tumor cell: Nf1 haploinsufficiency in the tumor environment
Cancer Cell
(2002)