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Lionel Groussin

Publications and source records attributed to Lionel Groussin.

At least 19 recordsLinked to original sources
PubMed2026

Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.

BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Humans↗
PubMed2006

Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome.

CONTEXT: In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol secretion is controlled by illegitimate membrane receptors. OBJECTIVE: The aim of the present study was to characterize the pharmacological properties and the transduction mechanisms of illegitimate receptors, i.e. receptors for serotonin (5-HT), gastric inhibitory polypeptide (GIP), and LH/human chorionic gonadotropin (hCG), expressed by AIMAH tissues to evaluate the role of ectopic receptors in the physiopathology of Cushing's syndrome. DESIGN: We used in vitro studies on cultured adrenal hyperplasia cells. SETTING: The setting was a university research laboratory. PATIENTS: AIMAH tissues (H1-H3) were removed from three patients previously screened for illegitimate receptors. MAIN OUTCOME MEASURE(S): The main outcome measures were steroidogenic and electrical activities of cultured adrenal hyperplasia cells. RESULTS: In vitro studies showed that the corticotropic effect of 5-HT was mediated by ectopic 5-HT7 receptors in H1 and H2. GIP and hCG stimulated cortisol production via activation of cAMP-dependent protein kinase A in H2. On the contrary, the protein kinase A inhibitor H-89 did not affect hCG-induced cortisol production in H3. Activation of 5-HT7 or GIP receptors enhanced T-type calcium current in H1 or H2 and H3, respectively. In addition, GIP reduced the amplitude of transient and sustained potassium currents in H2. Conversely, hCG did not modify T-type calcium current in H3. CONCLUSIONS: These data show that, besides their coupling to the cAMP pathway, illegitimate adrenal receptors can activate additional transduction mechanisms, including modulation of membrane channels.

Adenylyl Cyclases↗
PubMed2006

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients.

CONTEXT: Adrenocortical carcinomas (ACC) are rare tumors with a poor prognosis. Few reports concerning large and homogeneous series are available. OBJECTIVE: We aimed to determine the clinical characteristics and outcome of ACC and to identify prognostic factors. DESIGN AND SETTING: This study is a descriptive and multivariate analysis of a cohort from a single endocrinology center. PATIENTS: A total of 202 consecutive patients with ACC were studied. RESULTS: The sex ratio (female to male) was 2.7. Mean age at diagnosis was 44 +/- 16 yr (range, 11-88 yr). We found that 154 patients (76%) had hypersecreting tumors [mostly cortisol and androgens (47%), cortisol alone (27%), or androgens alone (6%)] and 43 patients (21%) had metastases at diagnosis. At initial staging or during follow-up, 85 patients (42%) had liver metastases, 79 patients (39%) had lung metastases, and 20 patients had bone metastases (10%). The survival rate was 37% at 5 yr. Multivariate analysis identified the following independent prognostic factors associated with shorter survival: older age at diagnosis [hazard ratio (HR), 1.03; P < 0.0001], initial MacFarlane extension stages 3 (HR, 4.42; P = 0.005) and 4 (HR, 7.93; P < 0.0001), and cortisol hypersecretion (HR, 3.90; P < 0.0001). Treatment with 1,1-dichlorodiphenildichloroethane (o,p'DDD) in the 3 months after surgery increased the survival rate of patients with cortisol-secreting tumors (HR, 0.40; P = 0.04). CONCLUSION: This study highlights the better prognosis of ACC diagnosed at a noninvasive local stage, the particularly poor prognosis of patients with cortisol-secreting tumors, and the beneficial effect of o,p'DDD therapy in this subgroup of patients.

Adrenal Cortex Neoplasms↗
PubMed2006

A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome, can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas, and endocrine tumors or be isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC and iPPNAD, but with no apparent genotype-phenotype correlation. OBJECTIVE: The objectives of the study were a detailed phenotyping for CNC manifestations in 12 kindreds bearing the same PRKAR1A mutation and a study of the consequences of the mutation and a potential founder effect. DESIGN: The study consisted of descriptive case reports. SETTING: The study was conducted at two referral centers. PATIENTS: The patients described in this study were referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently iPPNAD. RESULTS: We describe a 6-bp polypyrimidine tract deletion [exon 7 IVS del (-7-->-2)] in 12 unrelated kindreds that were referred for Cushing syndrome due to PPNAD. Nine of the patients had no family history; in two, there was a family history of iPPNAD. Only one patient met the criteria for CNC. Relatives carrying the same mutation had no manifestations of CNC or PPNAD, suggesting a low penetrance of this PRKAR1A defect. A founder effect was excluded by extensive genotyping of chromosome 17 markers. CONCLUSIONS: In conclusion, a small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly iPPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.

Adolescent↗
PubMed2006

PRKAR1A mutations in primary pigmented nodular adrenocortical disease.

Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare primary bilateral adrenal defect causing corticotropin-independent Cushing's syndrome. It occurs mainly in children and young adults. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. PPNAD is most often diagnosed in patients with Carney complex (CNC), but it can also be observed in patients without other manifestations or familial history (isolated PPNAD). The CNC is an autosomal dominant multiple neoplasia syndrome characterized by the association of myxoma, spotty skin pigmentation and endocrine overactivity. One of the putative CNC genes has been identified as the gene of the regulatory R1A subunit of protein kinase A (PRKAR1A), located at 17q22-24. Germline heterozygous inactivating mutations of PRKAR1A have been reported in about 45% of patients with CNC, and up to 80% of CNC patients with Cushing's syndrome due to PPNAD. Interestingly, such inactivating germline PRKAR1A mutations have also been found in patients with isolated PPNAD. The hot spot PRKAR1A mutation termed c.709[-7-2]del6 predisposes mostly to isolated PPNAD, and is the first clear genotype/phenotype correlation described for this gene. Somatic inactivating mutations of PRKAR1A have been observed in macronodules of PPNAD and in sporadic cortisol secreting adrenal adenomas. Isolated PPNAD is a genetic heterogenous disease, and recently inactivating mutations of the gene of the phosphodiesterase 11A4 (PDE11A4) located at 2q31-2q35 have been identified in patients without PRKAR1A mutations. Interestingly, both PRKAR1A and PDE11A gene products control the cAMP signaling pathway, which can be altered at various levels in endocrine tumors.

Adrenal Cortex Diseases↗
PubMed2006

Mechanisms of disease: adrenocortical tumors--molecular advances and clinical perspectives.

Most adrenocortical tumors are benign, unilateral, adrenocortical adenomas that are often discovered incidentally. Adrenocortical cancer is rare. Exceptionally, adrenocortical tumors can be bilateral. Although most adrenocortical tumors occur sporadically, they may also feature in congenital and/or familial disease. The identification of germline genetic defects in familial diseases associated with adrenocortical tumors helped to define the somatic alterations in sporadic disease: for example, overexpression of insulin-like growth factor 2 and alterations at the 11p15 locus (observed in Beckwith-Wiedemann syndrome) are also found in most adrenocortical cancers. Similarly, inactivating mutations of the TP53 gene, located at 17p13 (observed in Li-Fraumeni syndrome), can also be found at the somatic level in sporadic adrenocortical cancers, as can 17p13 allelic losses. Components of the cyclic AMP signaling pathway--for example, adrenocorticotropic hormone receptors and other membrane receptors, Gs proteins and protein kinase A--can be altered to various degrees in adrenocortical tumors. More recently, gene profiling and genetic studies have shown that the Wnt-beta-catenin signaling pathway is frequently activated in adrenocortical tumors. These research findings already have profound implications for clinical management of patients with adrenocortical tumors, for example in unraveling the genetic origin of the disease in some patients, and in the development of molecular markers for diagnosis and prognosis. The new findings should also help in the development of new therapeutic options.

Adrenal Cortex Neoplasms↗
PubMed2005

Adrenal pathophysiology: lessons from the Carney complex.

The Carney complex (CNC) is a dominantly inherited syndrome responsible mainly for spotty skin pigmentation (lentiginosis), endocrine overactivity, and cardiac myxomas. Adrenocorticotropic hormone independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is a main characteristic of CNC. PPNAD is a very rare cause of Cushing's syndrome due to a primary bilateral adrenal defect that can be also observed in some patients without other CNC manifestations nor familial history. One of the putative CNC genes, located on 17q22-24, has been identified as the regulatory subunit R1A of protein kinase A (PRKAR1A). Heterozygous inactivating mutations of PRKAR1A have been reported initially in about 45% of the CNC index cases and could be found in about 80% of the CNC families presenting mainly with Cushing's syndrome. PRKAR1A is a key component of the cyclic AMP signaling pathway that has been implicated in endocrine tumorigenesis and could, at least partly, function as a tumor suppressor gene. Interestingly, patients with isolated PPNAD and no familial history of CNC can also present a germline de novo mutation of PRKAR1A. Somatic mutations of PRKAR1A have been found in PPNAD as a mechanism of inactivation of the wild-type allele, in a patient already presenting a germline mutation, and in a subset of sporadic secreting adrenocortical adenomas with clinical, hormonal, and pathological features quite similar to PPNAD. This review will summarize the recent findings on CNC from the perspective of the pathophysiology of adrenal Cushing's syndrome and PPNAD.

Adrenal Cortex Diseases↗
PubMed2005

Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors.

Adrenocortical cancer is a rare cancer with a very poor prognosis. The genetic alterations identified to date in adrenocortical tumors are limited. Activating mutations of the Wnt signaling pathway have been observed in more frequent cancers, particularly digestive tract tumors. We investigated whether Wnt pathway activation is involved in adrenocortical tumorigenesis. In a series of 39 adrenocortical tumors, immunohistochemistry revealed abnormal cytoplasmic and/or nuclear accumulation of beta-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the beta-catenin gene was shown in 7 of 26 adrenocortical adenomas and in 4 of 13 adrenocortical carcinomas; these mutations were observed only in adrenocortical tumors with abnormal beta-catenin accumulation and most were point mutations altering the Ser45 of exon 3 (in the consensus GSK3-beta/CK1 phosphorylation site). Functional studies showed that the activating Ser45 beta-catenin mutation found in the adrenocortical cancer H295R cell line leads to constitutive activation of T-cell factor-dependent transcription. This is the first molecular defect to be reported with the same prevalence in both benign (27%) and malignant (31%) adrenocortical tumors. beta-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, beta-catenin alterations are more frequent in nonfunctioning tumors, suggesting that beta-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of beta-catenin in adrenocortical carcinomas suggests that other alterations might also be involved. This finding may contribute to new therapeutic approaches targeting the Wnt pathway in malignant adrenocortical tumors, for which limited medical therapy is available.

Adrenal Cortex Neoplasms↗
PubMed2004

In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism.

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1-H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing's syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.

Adrenal Glands↗
PubMed2004

18F-fluorodeoxyglucose positron emission tomography as a diagnostic tool for malignancy of adrenocortical tumours? Preliminary results in 13 consecutive patients.

DESIGN: This study is a preliminary report on 18F-fluorodeoxyglucose (18F-FDG) uptake for the characterization of hypersecretory or non-hypersecretory adrenocortical masses in patients without known neoplastic disease, thereby minimizing the presence of adrenal metastases, and without phaeochromocytoma, in comparison with computed tomography (CT) scanning and with iodocholesterol scintigraphy. METHODS: Thirteen consecutive patients with an adrenal mass scheduled to have surgery, underwent hormonal exploration, a CT scan for tumour size measurement and an 18F-FDG positron emission tomography scan. Eleven of these patients also had unenhanced density measurement at CT scan and iodocholesterol scintigraphy. RESULTS: CT-scanned adrenal masses ranged in size from 2.2 to 10 cm; attenuation value was <10 Hounsfield units (HUs) in two cases and >10 HU in nine. All benign lesions demonstrated iodocholesterol uptake. In the case of malignant tumours, results were non-homogeneous: no uptake, uptake and non-informative scintigraphy. All patients with an adrenocortical carcinoma had positive adrenal 18F-FDG uptake (n=3), one had a liver metastasis with positive 18F-FDG uptake, one showed 18F-FDG uptake in an adrenal metastasis from an unknown primary kidney tumour. All patients with a benign adrenocortical lesion had negative 18F-FDG uptake (n=9). Patients' lesions were hypersecretory (n=5), or non-hypersecretory (n=8), regardless of the pathology. CONCLUSION: This short preliminary study indicates that 18F-FDG gave a correct classification of tissue characterization with accurate identification of malignant lesions, as well as the disease stage (metastasis or primary). These promising preliminary results on adrenocortical lesions, seldom studied with 18F-FDG, are to be confirmed in larger series.

Adrenal Cortex↗
PubMed2003

Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity.

Germ-line protein kinase A (PKA) regulatory-subunit type-Ialpha (RIalpha; PRKAR1A)-inactivating mutations and loss-of-heterozygosity (LOH) of its 17q22-24 locus have been found in Cushing syndrome (CS) caused by primary pigmented nodular adrenocortical disease (PPNAD). We examined whether somatic 17q22-24, PRKAR1A, or PKA changes are present in 44 sporadic adrenocortical tumors (29 adenomas and 15 cancers); 26 of these tumors were responsible for CS. A probe containing the PRKAR1A gene-mapped by fluorescent in situ hybridization to 17q22-24-and corresponding microsatellite markers were used to study allelic losses; PRKAR1A was sequenced in all samples. 17q22-24 losses were seen in 23 and 53% of adenomas and cancers, respectively. In three tumors, somatic, PRKAR1A-inactivating mutations were identified: (a) a nonsense mutation in exon 6 (A751G); (b) a splicing mutation (9IVS-1G/A); and (c) a transition (1050T>C) followed by a 22-bp deletion, also in exon 9; all predicted premature RIalpha protein terminations. Quantitative message and protein studies showed RIalpha down-regulation in tumors with genetic changes; their cortisol secretion pattern was similar to that of PPNAD, and they had higher PKA activity by enzymatic studies. We conclude that somatic allelic losses of the 17q22-24 region, PRKAR1A-inactivating mutations or down-regulation, and corresponding PKA activity changes are present in at least some sporadic adrenocortical tumors, especially those with a PPNAD-like clinical presentation of CS.

Adrenal Cortex Neoplasms↗
PubMed2003

Aberrant receptor-mediated Cushing's syndrome.

Multiple alterations of G-protein-coupled receptors and G-proteins regulating intracellular transduction signal have been described in endocrine tumours. In Cushing's syndrome, aberrant or 'illicit' expression of membrane receptors (mainly G-protein-coupled receptors) has been observed in adrenal adenomas and adrenocorticotropic hormone (ACTH)-independent macronodular bilateral adrenal hyperplasia. The best characterized example to date is the aberrant expression of the gastric inhibitory polypeptide receptor that causes 'food-dependent hypercortisolism'. Aberrant expression of the luteinizing hormone, 2-adrenergic, interleukin receptors have also been reported. The level of expression of the vasopressin V1a receptor correlates with the direct (ACTH-independent) cortisol response to vasopressin.

Animals↗
PubMed2003

Transcription factor 3',5'-cyclic adenosine 5'-monophosphate-responsive element-binding protein (CREB) is decreased during human adrenal cortex tumorigenesis and fetal development.

Various cellular and molecular alterations of the cAMP pathway have been observed in adrenal Cushing syndrome. We recently reported the loss of cAMP-responsive element-binding protein (CREB) expression in the adrenocortical cancer cell line H295R. CREB is the major nuclear target of the cAMP pathway. This study therefore aimed to analyze the status of the CREB protein in various types of human adrenocortical tumors and normal fetal adrenal cortex. CREB protein status was studied by Western blotting in adrenocortical adenomas (AAs, n = 27) and adrenocortical carcinomas (ACs, n = 24). A decrease of CREB protein was noticed in the majority of the adrenocortical tumors. The dramatic decrease in CREB protein levels was more pronounced in ACs than in AAs. Levels of the phosphorylated form of CREB were also low in adrenocortical tumors, with a greater decrease in ACs than in AAs. EMSAs also showed decreases in the amounts of CREB- containing complexes in nuclear extracts from adrenocortical tumors. The secretory status of adenomas was strongly correlated with CREB levels, significantly lower in nonfunctioning AAs (n = 9) than in functioning AAs (n = 9). CREB levels, determined by Western blotting and immunohistochemistry, were very low in the fetal zone of human fetal adrenal cortex, whereas they were normal in the definitive zone. In tumors, adrenocortical cells in several zones were weakly immunohistochemically stained for CREB, whereas CREB was uniformly detected in nonendocrine cell nuclei (e.g. vascular cells, fibroblasts). These results suggest that the absence of CREB may be linked to the development of a highly aggressive tumor with a dedifferentiated benign (nonfunctioning AA) or malignant (AC) phenotype. These findings highlight the similarities between the normal human fetal adrenal gland and adrenal cancers previously observed in terms of parallelism in IGF-II production.

Adolescent↗
PubMed2002

Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD.

We studied 11 new kindreds with primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex (CNC) and found that 82% of the kindreds had PRKAR1A gene defects (including seven novel inactivating mutations), most of which led to nonsense mRNA and, thus, were not expressed in patients' cells. However, a previously undescribed base substitution in intron 6 (exon 6 IVS +1G-->T) led to exon 6 skipping and an expressed shorter PRKAR1A protein. The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at the nuclear level. This is the first demonstration of an inactivating PRKAR1A mutation being expressed at the protein level and leading to stimulation of the PKA pathway in CNC patients. Along with the lack of allelic loss at the PRKAR1A locus in most of the tumors from this kindred, these data suggest that alteration of PRKAR1A function (not only its complete loss) is sufficient for augmenting PKA activity leading to tumorigenesis in tissues affected by CNC.

Adenocarcinoma↗
PubMed2002

cAMP pathway alterations from the cell surface to the nucleus in adrenocortical tumors.

The cyclic AMP (cAMP) pathway plays a major role in the development of endocrine tissues and various molecular defects of key components of this pathway (G protein, receptors, PKA, ...) have been observed in endocrine tumors. Hypersecretion of adrenocorticotropin hormone (ACTH), the key activator of the cAMP pathway in adrenal cortex, is associated with adrenocortical hyperplasia and cortisol oversecretion (Cushing's syndrome). The best example of "illegitimate" membrane receptors expression reported is the abnormal expression of the adenylyl cyclase activating gastric inhibitory peptide receptor (GIP-R) in ACTH-independent Cushing's syndrome (ACS). We have observed that ectopic expression of the GIP-R is frequent in ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH), rare in benign adrenal adenoma (AA), but seems absent in Adrenal Cancer (AC). In vivo systematic screening of AIMAH shows at least one abnormal response of cortisol (suggesting "illegitimate" membrane receptor expression) in almost all patients. Somatic and germ line inactivating mutations of PRKAR1 (regulatory subunit R1A of PKA) can be observed in patient with isolated primary pigmented nodular adrenocortical disease (PPNAD) and AA responsible for ACS. At the nuclear level, the cAMP pathway regulates transcription mainly by PKA-dependent phosphorylation of the cyclic AMP response element binding (CREB) family of transcription factors (CREB, CREM, and ATF-1). Cyclic AMP response element binding protein (CREB) is expressed in normal adrenal cortex. Alterations of CRE binding proteins with loss of CREB expression and compensatory overexpression of CREMtau is observed in the human adrenocortical cancer cell line H295R. Similar alterations are found at the protein level in human malignant adrenocortical tumors. In conclusion, various alterations leading to activation or inactivation of key components of the cAMP signaling pathway can be observed in adrenocortical tumorigenesis.

Adrenal Cortex Neoplasms↗
PubMed2002

Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a cause of ACTH-independent Cushing's syndrome. This condition can be difficult to diagnose because hypercortisolism may be periodic and adrenal imaging may not demonstrate an adrenal tumor. PPNAD can be part of the Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome. Germline mutations of the regulatory subunit R1A of PKA (PRKAR1A) have been observed in about 45% of CNC kindreds. To improve our understanding of sporadic PPNAD and develop a potential diagnostic tool, we investigated the genetics of patients with sporadic and isolated PPNAD. Patients undergoing surgery for bilateral ACTH-independent Cushing's syndrome in whom pathological examination revealed PPNAD were subjected to endocrinological investigations and a systematic search for other manifestations of CNC. The PRKAR1A gene was sequenced using DNA from frozen adrenal tissues and leukocytes from three patients with sporadic isolated PPNAD and using leukocyte DNA from two additional patients. Different inactivating germline mutations of the PRKAR1A gene were found in the five patients. For three cases, study of the parents' DNA demonstrated a de novo mutation. One patient presented with an unusual 2.5-cm macronodule of the right adrenal mimicking an adrenal adenoma. A somatic 16-bp deletion of PRKAR1A gene was also found in this macronodule. Inactivating germline mutations of PRKAR1A are frequent in sporadic and isolated cases of PPNAD. The wild-type allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene. Thus, genetic analysis can be of help to the clinician in the diagnosis of this difficult form of adrenal Cushing's syndrome.

Adolescent↗