PubMed Health⌕ Search

Biomedical subjects

F Fallo

Publications and source records attributed to F Fallo.

At least 19 recordsLinked to original sources
PubMed2006

P450c17 deficiency: clinical and molecular characterization of six patients.

CONTEXT: The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development. OBJECTIVE: To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients. DESIGN AND PATIENTS: We examined six patients, five 46,XY, and one 46,XX (age 9-29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension. MAIN OUTCOME MEASUREMENTS: Genotype-phenotype correlation was measured. RESULTS: Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17alpha-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins. CONCLUSION: These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.

Adolescent↗
PubMed2006

Biochemical markers of endothelial activation in primary hyperparathyroidism.

Patients with primary hyperparathyroidism (PHPT) have impaired vasodilation both dependent and independent of endothelium. The aims of our study were to measure three different biochemical markers of endothelial activation, i. e., plasma thrombomodulin, soluble(s) E-selectin, and von Willebrand factor, in PHPT patients before and one year after successful parathyroidectomy, and to distinguish the potential effect of hypercalcemia and/or high parathyroid hormone from that of major cardiovascular risk factors (diabetes mellitus, hyperlipidemia, hypertension, obesity, smoking habit) on endothelial function. Twenty consecutive patients with PHPT subdivided into two groups according to the absence (n = 8) or presence (n = 12) of one or more risk factors, and fifteen healthy normocalcemic subjects were studied. Baseline thrombomodulin levels were similar in the groups with and without risk factors, and in controls. In contrast, sE-selectin and von Willebrand factor were higher in PHPT patients with risk factors than in those without risk factors (p < 0.05 and p < 0.01, respectively) and controls (p < 0.01). Neither thrombomodulin nor sE-selectin changed after parathyroidectomy in either PHPT group. Plasma von Willebrand factor decreased (p < 0.01) in patients without risk factors, while persisting at high levels in patients with risk factors. In conclusion, in spite of a limitation due to the small number of patients, our study suggests that classic cardiovascular risk factors seem to be the main determinants for the high plasma levels of sE-selectin and vWF in PHPT. Together with unaltered thrombomodulin and sE-selectin levels, a plasma vWF decrease after parathyroidectomy might reflect a specific mechanism of its endothelial calcium- and/or PTH-stimulated secretion in some PHPT patients without risk factors. Whether a vWF reduction after parathyroidectomy may be used as a biochemical index for improved endothelial function in PHPT patients without risk factors has yet to be demonstrated in larger studies.

Biomarkers↗
PubMed2005

Adrenal incidentaloma in pregnancy: clinical, molecular and immunohistochemical findings.

Adrenal incidentalomas detected during pregnancy are very rare, and the natural history of these tumors during gestation is unknown. We report a case of a pregnant woman with an adrenal mass discovered serendipitously, who was followed-up during gestation and underwent adrenalectomy shortly after delivery. This allowed the evaluation of both the clinical outcome and the molecular/immunohistochemical correlates. Estrogens may indeed influence the function and proliferation of human adrenal cells, and a state of circulating estrogen excess can represent an in vivo model to test their effect on the adrenals. No evidence of adrenal change in morphology and function was found in our patient throughout pregnancy, as shown by adrenal ultrasound imaging and adrenal hormone measurements. Four months after delivery, the patient underwent laparoscopic right adrenalectomy, and pathologic analysis revealed a 2.7 cm benign adrenocortical adenoma. The diameter of the adrenal mass at ultrasonography correlated highly with post-partum mass diameter measured by abdominal computed tomography (CT). Quantitative expression of both ERalpha and ERbeta by real-time RT-PCR analysis and Western blotting findings did not differ among adenoma, normal adjacent adrenal and normal adrenal control tissues. This case of an adrenal incidentaloma discovered during pregnancy shows that a close observation with endocrine investigations and ultrasonography could be an appropriate approach, delaying the decision of surgical intervention after delivery. Estrogen receptor mRNA levels in the adrenal mass similar to those observed in normal adrenals suggest that estrogen oversecretion during pregnancy was not a risk factor for tumor progression.

Adrenal Gland Neoplasms↗
PubMed2005

Shift from Conn's syndrome to Cushing's syndrome in a recurrent adrenocortical carcinoma.

OBJECTIVE: Adrenocortical tumors may originate from the zona glomerulosa, zona fasciculata, or zona reticularis and be associated with syndromes due to overproduction of mineralocorticoids, glucocorticoids, or androgens respectively. We report an unusual case of recurrent adrenocortical carcinoma (ACC), which seems to contradict the paradigm of functional adrenal zonation. CASE REPORT: A male patient presented with severe primary aldosteronism due to an ACC, which relapsed after adrenalectomy and adjuvant mitotane therapy. After removal of the tumor recurrence and eight cycles of chemotherapy with etoposide, doxorubicin and cisplatin, the patient presented again with ACC masses, but in association with overt Cushing's syndrome and normal aldosterone levels. METHODS AND RESULTS: Extensive pathologic examination showed that this shift in steroid hormone production was paralleled by an attenuation of tumor cell atypia and polymorphism, whereas gene expression profile analysis demonstrated a change in expression of adrenal steroidogenic enzymes. Moreover, cancer progression was associated with overexpression of the inhibin-alpha subunit, which could have contributed to the phenotypic changes. CONCLUSIONS: This case of recurrent ACC demonstrates that adrenocortical cells can reverse their differentiation program during neoplastic progression and change their specific hormone synthesis, as a consequence of modifications in the expression profile of steroidogenic enzymes and cofactors. We hypothesize that this shift in steroid hormone secretion is a consequence of chromosome amplification induced by chemotherapy. These findings, besides opening new perspectives to study adrenocortical cell plasticity and potential, demonstrate how conventional clinical and pathologic evaluation can be combined with genomic analysis in order to dissect thoroughly the biology of cancer.

Adrenal Cortex Neoplasms↗
PubMed2005

Antiestrogens upregulate estrogen receptor beta expression and inhibit adrenocortical H295R cell proliferation.

The molecular mechanisms involved in adrenocortical tumorigenesis are still not completely understood. In this study, using the H295R cell line as a model system, we investigated the role of estrogens and estrogen receptor (ER) alpha and ER beta in the growth regulation of adrenocortical tumors. We demonstrated that H295R cells are able to convert androgens to estrogens by a constitutive expression of active cytochrome P450 aromatase protein and express ER beta to a greater extent than ER alpha. Moreover, physiological concentrations of 17beta-estradiol (E2) determined an increase of thymidine incorporation, suggesting the presence of an autocrine mechanism in maintaining H295R cell proliferation. Evaluating the response to ER antagonists like 4-hydroxytamoxifen (OHT) and ICI 182 780 (ICI), we observed an up-regulation of ER beta and a dose-dependent inhibition of H295R cell proliferation. Whereas ICI determined the growth arrest of H295R cells, OHT induced morphological changes that were characteristic of apoptosis. According to the above-mentioned observations, OHT but not ICI clearly induced a marked expression of FasL and the cleavage of both caspase-8 and caspase-3. Interestingly, the apoptotic effects of OHT in H295R cells may be consequent to the enhanced levels of ER beta which stimulate the expression of FasL interacting with activating protein (AP)-1 sites located within its promoter sequence. In conclusion, we have demonstrated that H295R cells are able to transform androgens to estrogens that activate an autocrine mechanism, mediated by their own receptors, and contribute to regulate the proliferation of these cells. Moreover, this study points towards a role for ER beta as an important mediator of the repressive effects exerted by antiestrogens on H295R cells; however, further studies are needed to clarify its role in the control of adrenocortical cell proliferation and on the potential benefits of antiestrogens for treatment of adrenocortical cancer.

Adrenal Cortex↗
PubMed2004

The early diagnosis of multiple endocrine neoplasia type 1 (MEN 1): a case report.

We report the case of a patient presenting amenorrhea, hyperprolactinemia, headache and nuclear magnetic resonance (NMR) evidence of pituitary macroadenoma. The family history revealed that the patient's father had had a referred sporadic insulinoma, removed 25 yr before without evidence of other endocrine disorders. Physical examination evidenced a slight neck enlargement. Among biochemical and endocrinological assays performed, only hyperprolactinemia was observed. Neck ultrasonography (US) revealed a parathyroid enlargement and a 99mTcO4/MIBI scan showed two hyperplasic lesions. Considering the diagnostic suspect of multiple endocrine neoplasia (MEN1), we performed abdominal US and NMR studies, showing a pancreatic lesion compatible with neuroendocrine tumor. A total body 111In-DTPA-d-Phe1 -octreotide scan (Octreoscan) was also carried out, evidencing no pituitary tumor uptake but high uptake of the abdominal lesion. After surgery, the histological examination confirmed the two parathyroid adenomas and four non-functioning pancreatic neuroendocrine tumors. When the patient was admitted for studying the pituitary lesion and for planning the opportune therapy, an early and partially subclinical stage of MEN1 was identified, potentially already clear but otherwise undiagnosed, and the genetic state of the patient's relatives, as possible carriers of DNA mutation, was checked. The DNA study for germline mutations confirmed the clinical diagnosis of MEN1 syndrome in the patient and evidenced the same MEN1 mutation in her father and twin sister. In this case report, we would like to underline that, still today, a correct anamnesis and physical examination are the cornerstone of clinical approach to the patient. Furthermore, initial good practice approach is necessary to plan the diagnostic iter, enabling clinicians to decide upon the best orientation and interpretation of the results among several complicated and expensive exams.

Adolescent↗
PubMed2004

Use of quantitative ultrasound of the hand phalanges in the diagnosis of two different osteoporotic syndromes: Cushing's syndrome and postmenopausal osteoporosis.

The aim of this study was to assess the ability of the quantitative ultrasound of the hand phalanges to detect different types of osteoporosis resulting from different pathogenetic mechanisms. For this purpose, postmenopausal and glucocorticoid-induced osteoporosis was studied. Thirteen female patients with Cushing's syndrome (CS) resulting from pituitary-dependent bilateral adrenal hyperplasia (10 patients) and from adrenal adenoma (3 patients), and 32 postmenopausal osteoporotic (OP) women, were examined. The two groups of patients were comparable for body mass index (BMI), but CS patients were significantly younger than OP ones (CS 44.5+/-11.6; OP: 73.9+/-3.6). All the patients had femoral neck bone mineral density (BMD) T-score less than -2.0. Cushing patients had a femoral neck BMD similar to that of OP patients (CS: 603+/-66 mg/cm2; OP: 628+/-69 mg/cm2; p=0.19). In contrast, amplitude-dependent speed of sound (AD-SoS) was significantly higher in CS patients than in OP patients (CS: 1997+/-91 m/s; OP: 1707+/-114 m/s; p<0.0001). By adjusting DXA and ultrasound parameters according to age, femoral neck BMD was significantly lower in CS patients and AD-SoS remained significantly higher than in OP patients. These findings indicate that these two different kinds of osteoporosis can be distinguished by ultrasonography and that ultrasound parameters alone cannot be used for evaluating skeletal status in CS patients.

Adenoma↗
PubMed2004

Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism.

In glucocorticoid-remediable aldosteronism (GRA), there is a large interfamily variation of phenotype. We report three subjects with GRA in a single family (parents, two brothers and two sisters), of whom only one (proband) displayed classical features of the mineralocorticoid excess. The proband was a man found to be hypertensive and hypokalaemic at the age of 24 years. Plasma renin activity was suppressed and plasma aldosterone was repeatedly elevated. Blood pressure and aldosterone levels normalized within 5 days of dexamethasone therapy. The presence of a chimaeric CYP11B1/CYP11B2 gene was demonstrated by long-PCR and Southern blotting (crossover site at the end of intron 3) in the proband, in the younger sister (sibling 1) and in the father. In these patients, sequencing of the chimaeric portion of CYP11B1 did not reveal any mutation, while sequencing of the chimaeric portion of CYP11B2 showed a V386A polymorphism in exon 7, known to cause only a minimal impairment of enzymatic activity. Sibling 1 was normotensive, normokalaemic and had normal PRA and aldosterone. The father had normal blood pressure and potassium, low-normal PRA and normal aldosterone. All three subjects had elevated levels of urinary 18-hydroxycortisol and 18-oxocortisol. Baseline 11-deoxycorticosterone (DOC), corticosterone (B) and aldosterone were high in the proband and normal in the father and sibling 1; 11-deoxycortisol (S) and cortisol (F) were normal. ACTH induced a normal increase of B, DOC, S and F, and an excessive aldosterone increase in all three patients. Abnormalities in the chimaeric portions of CYB11B1 or CYP11B2 genes did not account for the phenotypic disparity of the different members in a single GRA family. Altered regulation of the chimaeric gene may be responsible for differences in its activity.

Adult↗
PubMed2004

Bradykinin B2 receptor gene C-58T polymorphism and insulin resistance. A study on obese patients.

The bradykinin B2 receptor (B2R) gene is a candidate in the pathogenesis of insulin resistance, which often clusters with other abnormalities in metabolic syndrome. We investigated the distribution of the C-58T B2R gene polymorphism within a population of overweight/obese patients (BMI > or = 25 kg/m2) potentially characterised by different levels of insulin resistance. Patients with type 2 diabetes, dyslipidemia and hypertension were excluded in order to distinguish the effect of obesity on insulin sensitivity from that of confounding factors. Ninety-two unrelated adults (41 men and 51 women, aged 33.7 +/- 11.6 years) were recruited by random sampling from a general population evaluated for cardiovascular risk stratification. Measurements included BMI, waist circumference, body composition, blood pressure, serum leptin, and lipid profile. Insulin sensitivity was calculated according to the homeostasis model assessment (HOMA) method. C-58T genotypes--CC (n = 20), CT (n = 47) and TT (n = 25)--were determined by restriction fragment-length polymorphism PCR. Patients subdivided on the basis of C-58T polymorphism, showed no difference in any of the parameters examined, including HOMA index values, after adjustment for age, sex, BMI and waist circumference. The results indicate that the C-58T B2R gene polymorphism is not associated with different levels of insulin resistance within a population of obese patients.

Adult↗
PubMed2004

Technetium-99m sestamibi scintigraphy and helical CT together in patients with primary hyperparathyroidism: a prospective clinical study.

44 consecutive patients with confirmed primary hyperparathyroidism (HPT) undergoing surgery were prospectively enrolled in the study. There were 13 (29.5%) men and 31 (70.5%) women with an overall median age of 59 years (range 23-78 years). Prior to successful parathyroidectomy both (99)Tc(m)-sestamibi/(99)Tc(m)-pertechnetate subtraction scintigraphy (SS) and helical CT were performed, and the results of imaging studies were compared against intraoperative findings. Final histopathology showed 40 (90.9%) solitary parathyroid (PT) adenomata (median size 18 mm, range 8-40 mm), that were in an ectopic location in 13 (32.5%) patients. Moreover, 3 (6.8%) patients had multiglandular disease (one patient with two PT adenomata, two patients with PT hyperplasia), while one (2.3%) patient had a PT carcinoma. The sensitivity and positive predictive value were 86.0% and 97.4% for SS, 88.1% and 94.9% for CT, and 100% and 97.4% for the combination of SS and CT, respectively. Calcium and parathyroid hormone (PTH) serum levels, and the mean size of the removed PT glands of patients with false negative results were lower than that of those with true positive results, but the difference was not significant. Among patients with solitary PT tumours (N=41) the sensitivity was 88.1% and 90.3% for SS and CT-scan, respectively. In conclusion, our study confirms the usefulness of SS, which should be the initial test for patients undergoing parathyroidectomy. However, the strategy of performing two tests in each patient with primary HPT could be of limited utility when the initial SS is positive.

Adenoma↗
PubMed2004

Life events in the pathogenesis of hyperprolactinemia.

OBJECTIVE: Little is known about the relationship between recent life events and onset of hyperprolactinemia, despite the well-known effect of acute psychological stress on prolactin levels in healthy subjects. Recent life events in patients with hyperprolactinemia compared with healthy controls were investigated. DESIGN: Case-control study. METHODS: Fifty-two consecutive patients with hyperprolactinemia (45 females/7 males; mean age 34.9+/-10.1 years, range 18-60 years) and 52 healthy subjects matched for socio-demographic variables were studied. Nineteen patients (18 females/1 male) had no pituitary tumor and were diagnosed as suffering from idiopathic hyperprolactinemia. Patients with additional pathology or with high prolactin due to medications were excluded. All patients were interviewed by Paykel Interview for Recent Life Events while on remission after surgery or pharmacological treatment. The time period considered was the year preceding the first signs of hyperprolactinemia, and the year before interview for controls. RESULTS: Patients with hyperprolactinemia reported significantly more life events than control subjects (P<0.001). The same significant difference compared with controls applied to patients with (n=16) and without (n=36) depression. All categories of events (except events that were likely to be under the subject's control) were significantly more frequent. There were no significant differences between patients with prolactinoma (n=33) and those with idiopathic hyperprolactinemia (n=19). CONCLUSIONS: Within the complexity of phenomena implicated in the pathogenesis of hyperprolactinemia, our findings emphasize a potential role of emotional stress in either prolactin-secreting pituitary tumors or idiopathic hyperprolactinemia. Appraisal of life stress may have implications in clinical assessment (e.g. functional hyperprolactinemia) and decisions (e.g. termination of long-term pharmacological treatment).

Adolescent↗
PubMed2004

Differential expression of menin in sporadic pituitary adenomas.

Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).

Adenoma↗
PubMed2002

Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas.

BACKGROUND: The presence and pathophysiological role of CYP11B1 (11beta-hydroxylase) gene in the zona glomerulosa of human adrenal cortex is still controversial. METHODS: In order to specifically quantify CYP11B1, CYP11B2 (aldosterone synthase) and CYP17(17alpha-hydroxylase) mRNA levels, we developed a real-time RT-PCR assay and examined the expression in a series of adrenal tIssues, including six normal adrenals from patients adrenalectomized for renal cancer and twelve aldosterone-producing adenomas (APA) from patients with primary aldosteronism. RESULTS: CYP11B1 mRNA levels were clearly detected in normal adrenals, which comprised both zona glomerulosa and fasciculata/reticularis cells, but were also measured at a lower range (P<0.05) in APA. The levels of CYP11B2 mRNA were lower (P<0.005) in normal adrenals than in APA. CYP17 mRNAlevels were similar in normal adrenals and in APA. In patients with APA, CYP11B2 and CYP11B1 mRNA levels were not correlated either with basal aldosterone or with the change from basal aldosterone in response to posture or to dexamethasone. No correlation between CYP11B1 mRNA or CYP11B2 mRNA and the percentage of zona fasciculata-like cells was observed in APA. CONCLUSIONS: Real-time RT-PCR can be reliably used to quantify CYP11B1 and CYP11B2 mRNA levels in adrenal tIssues. Expression of CYP11B1 in hyperfunctioning zona glomerulosa suggests an additional formation of corticosterone via 11beta-hydroxylase, providing further substrate for aldosterone biosynthesis. CYP11B1 and CYP11B2 mRNA levels in APA are not related to the in vivo secretory activity of glomerulosa cells, where post-transcriptional factors might ultimately regulate aldosterone production.

Adenoma↗
PubMed2001

Cushing's syndrome.

During the past 30 years, there have been advances in understanding of the pathogenesis of Cushing's syndrome and in differential diagnosis of its various forms. Improved diagnostic tests and procedures have increased the ability to recognise even mild hypercortisolism and have provided the means to obtain an accurate diagnosis. Despite these advances, the occurrence of unusual clinical presentations and laboratory shortcomings may produce diagnostic problems and challenge clinical intuition. This article reviews recent pathogenic views, new tests, and new diagnostic problems in the evaluation of Cushing's syndrome. Atypical clinical presentations of hypercortisolism and some laboratory shortcomings that may confuse the diagnosis of Cushing's syndrome are also reported.

Cushing Syndrome↗
PubMed2001

Recovery of bone mineral density after surgical cure, but not by ketoconazole treatment, in Cushing's syndrome.

The aim of our study was to retrospectively assess the effect of treatment on bone mineral density (BMD) in patients with Cushing's syndrome. Nineteen patients (17 women, 2 men; mean age +/- SD, 41 +/- 10 years; preoperative duration of disease 20 +/- 15 months) were studied. Six patients had a cortisol-producing adenoma and 13 had pituitary-dependent bilateral adrenal hyperplasia. BMD of the lumbar spine (L2-L4) was measured by dual-energy X-ray absorptiometry just before and 1-10 years after adrenalectomy or pituitary adenomectomy. Patients were divided in two groups. The first group of 9 patients (6 adrenal and 3 pituitary adenomas; group A) included those treated successfully by surgery ( > 5 years follow-up in the case of pituitary surgery). The second group of 10 patients (group B) included those treated with the steroidogenesis inhibitor ketoconazole, 300-600 mg/day, after unsuccessful pituitary surgery. In group A, restoration of normal cortisol was associated with a significant increase in BMD (from 829 +/- 112 mg/cm2 to 952 +/- 107 mg/cm2; p = 0.002). In group B, no changes in BMD were observed (from 857 +/- 160 to 847 +/- 163 mg/cm2), in spite of markedly decreased or normalized cortisol levels during ketoconazole treatment. These findings indicate that definitive correction of hypercortisolism restores BMD to normal levels in patients with Cushing's syndrome. In patients treated with ketoconazole after unsuccessful pituitary surgery, even when normalization of cortisol levels was achieved, BMD remained low. This would suggest an interfering effect of this drug on bone metabolism.

Absorptiometry, Photon↗
PubMed2001

Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production.

OBJECTIVE: 11beta-Hydroxylase and aldosterone synthase are two highly homologous genes involved in different forms of human hypertension and in different animal models of hypertension. It has been shown that the conservative substitution D147E in the human CYP11B2 gene results in an increased production of corticosterone and aldosterone in vitro. A gene conversion between the CYP11B1 and CYP11B2 genes could be responsible for such a substitution. METHODS: In this study we investigated the presence of the mutation D147E of CYP11B2 in a group of 128 patients with primary aldosteronism, 68 patients with essential hypertension and increased corticosterone production and in 48 normal volunteers. RESULTS AND CONCLUSIONS: We did not identify any patient carrying this mutation, indicating that if it exists it is very rare and so has no relevance in determining the increased steroid excretion seen in some subtypes of human hypertension.

Aged↗
PubMed2001

Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors.

OBJECTIVE: To evaluate the roles of the CDKN1C (P57KIP2) gene, which encodes for the cyclin-dependent kinase inhibitor CDNC, and the TP53 tumor suppressor gene in adrenal tumorigenesis, as a means of investigating the molecular basis of sporadic adrenal tumors, which is unknown. DESIGN: Screening for the presence CDKN1C and TP53 mutations and analyzing the expression pattern of CDNC, P53 and its downstream effector CDN1 (P21WAF1/CIP1) in a series of 79 sporadic adrenal tumors. METHODS: Single-strand conformation polymorphism and sequencing were used for mutation analysis of CDKN1C and TP53 in blood and adrenal tissue samples. In a subgroup of 48 tissues, CDKN1C expression was evaluated by RT-PCR and immunohistochemistry. Immunohistochemical analysis of P53 and CDN1 was performed. RESULTS: No somatic mutations of CDKN1C were found in the tumors analyzed, in spite of low/absent CDNC expression in adrenocortical adenomas and carcinomas. Mutations in the TP53 gene were present in 70% of adrenocortical carcinomas, associated with abnormal P53 and CDN1 expression, but not in benign neoplasms. In the normal adrenal cortex, CDNC expression was strictly nuclear and confined to the cortical zone (i.e. zona glomerulosa and reticularis), with no staining in the medulla. CONCLUSIONS: Mutations in the TP53 gene are frequent in adrenocortical carcinomas and might be used as a marker of malignancy. In the normal adrenal cortex, the zone-specific pattern of expression of CDNC suggests a role in adrenal differentiation.

Adrenal Gland Neoplasms↗