Genetics of adrenocortical tumors: gatekeepers, landscapers and conductors in symphony

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Abstract

The genetic and histopathological backgrounds of adrenocortical tumorigenesis remain poorly characterized. In other tissues, there is conclusive evidence that hyperplasia and adenomas precede cancer. In the adrenal, there are few clinical cases of either hyperplasia or adenoma associated with later development of cancer, and there are few biological studies that attempt to characterize this process molecularly. Current research focuses on the early lesions of the adrenal cortex because of their possible molecular link with carcinogenesis, and evidence of their frequent association with atypical forms of Cushing's and Conn's syndromes, obesity, hypertension and/or diabetes. These studies indicate a model for oncogenesis that is the same as that in other tissues. The rarity of adrenal cancer compared to benign lesions could be a clue to unique features of adrenocortical cells. It might also highlight the function of genes that are associated with endocrine tumors in the context of which the concept of gene ‘conductors’ is introduced here.

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.

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