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Mol Cell Endocrinol. Author manuscript; available in PMC 2010 March 5.
Published in final edited form as:
PMCID: PMC2668239



Over the course of the last 10 years, we have studied the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands. On the basis of this work, we propose an hypothesis on how adrenocortical tumors form and the importance of the cyclic AMP-dependent signaling pathway in this process. The regulatory subunit type 1-α (RIα) of protein kinase A (PKA), (the PRKAR1A gene) is mutated in most patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). Phosphodiesterase-11A (the PDE11A gene) and -8B (the PDE8B gene) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD. PKA effects on tumor suppression and/or development and the cell cycle are becoming clear: PKA and/or cAMP act as a coordinator of growth and proliferation in the adrenal cortex. Mouse models in which the respective genes have been knocked out see m to support this notion. Genome-wide searches for other genes responsible for adrenal tumors and related diseases are ongoing; recent evidece of the involvement of the mitochondrial oxidation pathway in adrenocortical tumorigenesis is derived from our study of rare associations such as those of disorders predisposing to adrenomedullary and related tumors (Carney triad, the dyad of paragangliomas and gastric stromal sarcomas or Carney-Stratakis syndrome, hereditary leiomyomatosis and renal cancer syndrome) which appear to be associated with adrenocortical lesions.

Keywords: Phosphodiesterases, multiple endocrine neoplasia, Carney Triad, Carney-Stratakis syndrome, fumarate hydratase

1. Introduction: adrenocortical tumorigenesis

Significant progress has been made through studies from our laboratory and other investigators on the understanding of molecular genetics of endocrine tumors such as adrenocortical tumors (ADT) (Stratakis, 2003). What was limited to TP53 gene’s involvement in adrenocortical cancer (ACC) in the early 1990s extends now from cAMP- to the Wnt-signaling pathways; a number of alterations have been detected at the genomic, transcript or protein levels (Bourdeau et al., 2004; Horvath et al., 2006, Bornstein and Hornsby, 2005). The multi-step model of tumorigenesis that had been described in other tissues, and that we first proposed for ADTs (Stratakis, 2003), is now widely accepted (Bernard et al., 2003). The notion of studying, first, benign hyperplasias and “cloning genes and identifying molecular pathways involved in the first steps of ADT formation” that we suggested in the early 1990s has paid off with the identification of the cAMP/PKA-signaling pathway as the main molecular route that when defective leads to benign ADTs and hyperplasias; Wnt-signaling abnormalities (present also in some hyperplasias), growth factor expression (i.e. IGF-II, IGFBPs), and cell cycle gene defects (TP53, CHEK2) are associated with large adenomas and ACC (de Fraipont et al., 2005) (Figure 1).

Figure 1
Tumorigenesis in the adrenal cortex, like in other endocrine (i.e. pituitary) and non-endocrine tissues (i.e. colon) is subject to a multi-step process, although not all steps are detected in pathologic specimens, nor it is necessary for all steps to ...

In this model, hyperplasias of the adrenal cortex remain the cornerstone of the elucidation of the molecular phenomena that culminate in cancer formation. This process does not necessarily precede linearly other steps (this may still happen rarely): one example of non-linear phenomena are those that happen in parallel in different cell types, such as the stroma and tumor cells. It is noteworthy that a recent autopsy study identified adrenal hyperplasia in 36% of the subjects studied (saeger et al., 1998). It is for this reason, first, that we continue to focus on the clinical, genetic and molecular identification of bilateral adrenocortical hyperplasias (BAH): elucidation of all genetic defects leading to BAH will assist us in understanding the first (and apparently common) steps that adrenocortical tissue undertakes towards any pathology. The second reason is that unlike adenomas and cancer, BAHs are to a much larger extent inherited or more directly due to genetic causes (Bourdeau and Stratakis, 2002); this allows for the more efficient use of gene mapping tools that take advantage of positional approaches based on SNPs and other family data in addition to classic cancer genetic techniques such as loss-of-heterozygosity (LOH). And, finally, BAHs associated with Cushing syndrome have a distinct biochemical phenotype of hypercortisolemia that we and others have striven to define with the development of proper testing; recently, we presented a tentative classification of all BAHs helped by the new genetic discoveries (Table 1) (Stratakis and Boikos, 2007).

Table 1
Bilateral adrenocortical hyperplasias leading to Cushing syndrome and molecular causes

2. Phosphodiesterases: extending the role of cAMP-signaling in adrenocortical tumors

In the year 2000, we identified the molecular cause of the most common among the micronodular BAHs, primary pigmented nodular adrenocortical disease (PPNAD) (Kirschner et al., 2000). PPNAD is characterized by small, pigmented nodules that are surrounded by mostly atrophic cortex in an otherwise normal-sized gland (Carney et al., 1985). Most cases of PPNAD, inherited or sporadic, are associated with Carney complex (CNC), a syndrome that causes abnormal skin and mucosal pigmentation in addition to a variety of tumors [myxomas of the skin, heart, breast and other sites, psammomatous melanotic schwannoma, growth hormone (GH)-producing pituitary adenomas, testicular Sertoli and Leydig cell neoplasms, thyroid tumors, breast adenomas, nevi, and, perhaps, colon and other cancers] (Stratakis et al., 2001). CNC shares features with multiple endocrine neoplasia (MEN) and lentiginosis syndromes, such as MEN 1 and Peutz-Jeghers syndrome (PJS), and other hamartomatoses (MRash and Stratakis, 2001). By linkage analysis we and others identified two loci harboring genes for CNC on 2p16 (CNC2) and 17q22-24 (CNC1) (Stratakis et al., 2001). We then identified the PRKAR1A gene from the CNC1 17q22-24 locus (Kirschner et al., 2000). PRKAR1A encodes the regulatory subunit type 1A (R1α) of PKA, a molecule that is the main regulator of this cAMP-dependent protein kinase, one of the most important regulatory pathways in cellular signaling (Amieux, 2002).

Following the identification of PRKAR1A gene mutations in PPNAD, we had, in addition to clinical and histopathological features, a molecular genetic marker that could be used to identify diagnostic subgroups of the BAH and CNC patients that we were working with (Table 1). This allowed us to identify significant genetic heterogeneity within patients that were previously thought to have one disease.

Before embarking on using the samples that were PRKAR1A-mutation-negative to search for other genes, we wanted to eliminate the possibility that genetic defects that would not be identifiable by sequencing were present. Fluorescent in situ hybridization (FISH) with bacterial artificial chromosome (BAC) probes containing the PRKAR1A gene did not show any large defects, but survey by restriction digestion and long-range PCR resulted in the identification of two chromosome 17q22-24 microdeletions among 36 PRKAR1A-mutation-negative unrelated kindreds (Horvath et al., 2008). Based on this study, one would expect that about 6% of PPNAD and/or CNC patients that do not have a coding sequence mutation may still have a defect of the PRKAR1A gene.

Among the remaining kindreds that did not have PRKAR1A mutations, we then used the clinical and histopathological criteria that we developed and are listed in Table 1 to identify subgroups of patients/families. First, we identified patients (10 kindreds) with micronodular adrenocortical disease (MAD) (Gunther et al., 2004). Prior to the identification of the PRKAR1A gene, MAD patients had been grouped together with those that had “classic” PPNAD, because even though pigment (lipofuscin) was not evident by regular microscopy, in some patients electron microscopy could identify pigment granules. It had been assumed, since most patients with MAD were very young (2 to 7 years old), that the lack of heavy pigmentation was a function of their age. However, following the identification of PRKAR1A, it became clear that almost none of these patients had PRKAR1A gene defects. Like PPNAD, MAD leads to corticotropin (ACTH)-independent hypercortisolism caused by small nodules randomly arising within the cortex of both adrenal glands of affected individuals. Most cases of non-pigmented MAD were isolated (iMAD – not associated with any other tumors or conditions), sporadic (patients did not have any family history) and occurred in very young children. Some patients had a presentation consistent with atypical Cushing syndrome; most patients were female; and, autosomal dominant inheritance could be documented in one kindred that had previously been mapped to the CNC2 locus (CAR14).

Since most patients were sporadic, we teamed with investigators from a private bioinformatics enterprise to apply novel software (EXEMPLAR®) for a GWA study that took into account the prior information of linkage to chromosome 2. Tetrads of samples were genotyped: the two unaffected parents, peripheral blood DNA and tumor DNA microdisected from the adrenal lesions of the proband; the single family (CAR14) and their tumor tissue were also genotyped. The Affymetrix® 10K genechip was used (the study was done in 2006). By a combination of association analyses and the detection of gene dosage alterations, loss-of-heterozygosity (LOH) and amplification events, the 2q31-33 was identified as potentially harboring a susceptibility locus along with the previously identified 2p16-15 locus and other loci in the genome including regions on 5q, 8q, and others (these data are available on line at These studies culminated in the identification of the phosphodiesterase (PDE) genes, PDE11A (Horvath et al., 2006) and, more recently, PDE8B (Horvath et al., 2008b) from the 2q and 5q13 areas. Ongoing search includes the study of candidate genes from the locations that had the highest linkage p values.

These published data and ongoing work suggest that PDE11A inactivating defects are found in increased frequency in a subgroup of patients with PPNAD, iMAD and other forms of BAH and possibly other adrenal and endocrine tumors (Horvath et al., 2006b). Two frameshift mutations disrupting the PDE11A4 adrenal-specific isoform protein (c.171Tdel/fs41X and c.1655_1657delTCTinsCC/fs15X) and a base pair substitution (c.919C>T p.R307X) were the first such PDE11A gene variants that were reported (Fig. 3); in addition, two missense substitutions that are relatively frequent polymorphisms of the PDE11A gene (c.2411G>A, p.R804H and c.2599C>G, p.R867G) were found in increased frequency among patients with adrenal lesions. We confirmed PDE11A gene mapping to the 2q31-35 by FISH and tumors from patients with PDE11A-inactivating mutations demonstrated 2q allelic losses (Libe et al., 2008) (Figure 2).

Figure 2
(a) PDE11A sequence defects in patients with adrenal disease 42: the upper (in red) bar shows the protein and its main PDE functional domains; the lower (in green) shows the location of the sequence defects in the 22-exon gene; R804H and R867G are relatively ...
Figure 3
A. Pictures of patient CAR559.03 with Cushing syndrome 43 B. Family CAR 559: the mutant allele (C) of the proband (CAR559.03) was inherited from her father (CAR559.01); her mother (CAR550.02) had normal PDE8B alleles; C. Midnight cortisol levels (in mg/dl) ...

PDE11A is a dual-specificity PDE catalyzing the hydrolysis of both cAMP and cGMP; it is expressed in several endocrine tissues (Boikos et al. 2008): the PDE11A gene, like that of other PDEs, has a complex organization: only the A4 splice variant is expressed in adrenal, whereas A1 is ubiquitous, and A2 and A3 have a more limited expression pattern.

PDE8B codes for a PDE that has the highest affinity to cAMP among all known PDEs (Conti and Beavo, 2007). The locus harboring PDE8B on 5q13 was also among the most likely regions to be associated with MAD in our GWA study and PDE8B was highly expressed in the adrenal gland. We sequenced the PDE8B-coding regions in all remaining patients with MAD and identified a single base substitution (c.914A>T or H305P) in a female (CAR559.03) who had Cushing syndrome (Figure 3, A-C) (Horvath et al, 2008). The patient inherited the mutation from her father, who was obese and had hypertension, abnormal midnight cortisol levels, and on computed tomography mild hyperplasia (Fig. 3, B-D). The c.914A>T substitution was not present in more than 2,000 control chromosomes and the H305P mutation affects an evolutionary conserved residue (Fig. 3, E and F). In vitro studies on HEK293 cells showed significantly higher cAMP levels after transfection with the mutant PDE8B indicating an impaired ability of the protein to degrade cAMP (Fig. 3G).

These studies identified mutations in a new class of genes, those coding for cAMP-binding PDEs, as predisposing to BAHs and possibly other adrenal tumors. The discovery reinforced the notion that aberrant cAMP signaling is tightly linked to genetic forms of cortisol excess that lead to Cushing syndrome. Ongoing work is aimed at testing other PDEs that bind cAMP for mutations in our patients. An important aspect of the PDE11A studies was the recent identification of 3 PDE11A-inactivating (protein-truncating) mutations in a population of control patients that are being followed for the development of cancer (the New York Cancer Project, NYCP) with a combined frequency of 1.6%. Two functional PDE11A missense substitutions, R804H and R867G, were present at much higher rates of 2.4% and 3%, respectively (Horvath et al., 2006b). These findings raised the possibility that carrying PDE11A gene defects has wider implications that go beyond a predisposition to adrenocortical hyperplasia or tumors (Libe et al., 2008).

3. Clinical and molecular elucidation of other conditions associated with adrenal tumors

As part of our efforts to clinically and molecularly elucidate all genetic forms of adrenocortical adenomatosis (Table 1), we have not limited our studies to PPNAD and MAD. We have also studied the main form of BAH in adults, massive macronodular adrenocortical disease or ACTH-independent macronodular adrenocortical hyperplasia (MMAD/AIMAH). The clinical complexity and genetic heterogeneity of MMAD/AIMAH appears to be at least as extensive as that of PPNAD, MAD and related disorders, as our microarray studies indicated. Although the importance of the cAMP-signaling pathway is again undisputable, from the ectopic expression of G-protein coupled receptors to the somatic mutations of the GNAS gene (coding for the Gsα Gs protein subunit) in McCune-Albright syndrome and sporadic cases of MMAD/AIMAH and the deletions of the PRKAR1A locus in MMAD nodules (Bourdeau et al., 2006), we have also demonstrated for the first time the involvement of the mitochondrial oxidation pathway in adrenocortical tumor formation: patients with fumarate hydratase (FH) defects and the hereditary leiomyomatosis and renal cancer syndrome (HLRCS) develop adrenocortical adenomas (Matyakhina et al., 2005); direct involvement of the FH gene in MMAD was shown in a patient with HLRCS.

In addition, recently, we described five unrelated families that had gastrointestinal tumors (GIST), paragangliomas (PGL) and occasionally ADTs (mostly adenomas or MMAD/AIMAH); the trait was inherited in an autosomal dominant manner (with incomplete penetrance) (Carney and Stratakis, 2002). The condition has been referred to as the dyad of “paraganglioma and gastric stromal tumors” or the “Carney-Stratakis syndrome or dyad” (Passini et al., 2008; McWhinney et al., 2007)) and is distinct from Carney Triad (PGL, GIST, pulmonary chondroma and other tumors, including ADTs) (Matyakhina et al., 2007). We found germline mutations of the genes encoding succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD that were known to be involved in inherited PGL and pheochromocytoma but were not previously involved in familial GIST or in ADTs (Passini et al., 2007). The patients did not have mutations of the KIT or platelet-derived growth factor receptor-alpha (PDGFRA) genes that have been associated with GIST55-59. Ongoing studies by an international consortium (that our laboratory participates in) are aimed at identifying the remaining genes for patients with Carney Triad who also get ADTs (mostly MMAD/AIMAH) (Matyakhina et al., 2007).


These studies were supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), NIH intramural project Z01-HD-000642-04 (to Dr. C. A. Stratakis).


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