Endocrine oncology (Bristol, England)最新文献

{"title":"Prevalence of growth hormone deficiency in brain tumor survivors: a systematic review and meta-analysis.","authors":"Tatiana Tselovalnikova, Ben Ponvilawan, Maria G Pavlova, Cynthia Flanagan, Sunpreet S Rakhra, Betty M Drees","doi":"10.1530/EO-25-0025","DOIUrl":"https://doi.org/10.1530/EO-25-0025","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the prevalence of growth hormone deficiency in patients who underwent cranial irradiation for brain tumors.</p><p><strong>Methods: </strong>Ovid Medline and Embase databases were used for review. Eligible studies were observational studies with brain tumor survivors who had growth hormone function evaluated after treatment at age ≥18 years. Patient data on disease prevalence were pooled using the random-effect, generic inverse variance method. The presence of publication bias was determined by Egger's test. Mann-Whitney U test, univariate and multivariate linear regression were used to determine the association and effect of covariates and growth hormone peak level.</p><p><strong>Results: </strong>After screening 3,355 relevant articles, seven studies were included. The pooled result showed that out of 3,489 patients who received radiation for brain tumors, regardless of age at the time of treatment, 50% developed growth hormone deficiency (95% CI 40-60%, <i>I</i> ² = 83%). Subgroup analysis based on the growth hormone peak level did not show differences between different cutoffs. Univariate linear regression using data from 27 patients showed that age at radiation and the time duration between radiation and the stimulation test (<i>P</i> = 0.03 and 0.002, respectively), but not radiation dose or sex, were significantly correlated with growth hormone peak level. After multivariate adjustment, only the time duration between radiation and the stimulation test was associated with decreased growth hormone peak level (<i>P</i> = 0.04).</p><p><strong>Conclusions: </strong>Half of brain tumor survivors develop growth hormone deficiency. A longer duration of follow-up is associated with higher risks of growth hormone deficiency. Lifelong follow-up is essential.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e250025"},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using routinely collected patient data to study the impact of type 2 diabetes on breast cancer.","authors":"Ayaan Khurshed, Gema Hernandez, Gavin Soady, Nalinie Joharatnam-Hogan, Daniel Morganstein","doi":"10.1530/EO-24-0039","DOIUrl":"https://doi.org/10.1530/EO-24-0039","url":null,"abstract":"<p><strong>Objective: </strong>Type 2 diabetes mellitus (T2DM) and cancer are prevalent conditions, with evidence linking T2DM to higher breast cancer incidence and mortality. However, it is uncertain whether excess mortality in breast cancer patients with diabetes is driven by cancer-related factors. This study aims to investigate overall survival (OS) and chemotherapy receipt post-surgery in women with diabetes and localised breast cancer.</p><p><strong>Methods: </strong>Cohorts were constructed from electronic patient records on TriNetX, a de-identified patient database. Three cohorts included women with diabetes stratified by localised breast cancer stage (1 & 2, 3 and all), compared to control groups without diabetes. Cohorts were propensity score matched for age, ethnicity, smoking status and BMI. OS and chemotherapy receipt were compared.</p><p><strong>Results: </strong>Patients with diabetes (<i>n</i> = 1,488) were significantly older, more likely to smoke and had higher BMIs than those without diabetes (<i>n</i> = 7,284). The unadjusted hazard ratio (HR) for OS across all cancer stages was 2.17 (95% CI: 1.90-2.485) and the adjusted HR was 1.69 (95% CI: 1.41-2.04). After further adjusting for vascular diseases, the HR for OS was 1.59 (95% CI: 1.32-1.92). No significant difference was found in chemotherapy receipt.</p><p><strong>Conclusion: </strong>We observed significantly poorer OS in women with breast cancer and diabetes across all stages, compared to those without diabetes. Importantly, this persisted after adjusting for confounders and cardiovascular diseases, supporting that diabetes directly influences cancer outcomes.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e240039"},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thieno[2,3-<i>b</i>]pyridine compounds potently inhibit prostate cancer growth and motility.","authors":"M A Alkheilewi, D A Leach, A Mohr, R M Zwacka, P Laissue, M Metodiev, C L Bevan, M Van Rensburg, L I Pilkington, D Barker, J Reynisson, G N Brooke","doi":"10.1530/EO-24-0082","DOIUrl":"https://doi.org/10.1530/EO-24-0082","url":null,"abstract":"<p><strong>Objective: </strong>Prostate cancer growth is dependent upon androgens and hence therapies often target this signalling axis. These therapies, for example the antiandrogen enzalutamide, are successful in the majority of men; however, resistance is inevitable and the tumour progresses to the castrate-resistant stage, a disease of unmet clinical need. Consequently, there is a great need for novel therapeutics for castrate-resistant prostate cancer. Thieno[2,3-<i>b</i>]pyridine compounds have shown promise as novel anti-cancer molecules, but little is known about their efficacy in prostate cancer. To address this, a panel of thieno[2,3-<i>b</i>]pyridine compounds was screened to identify those with cytostatic/cytotoxic activity in prostate cancer.</p><p><strong>Methods: </strong>The effect of the compounds upon prostate cancer proliferation and motility was assessed in a panel of cell lines representing different stages of the disease and non-tumorigenic controls. The effect of the compounds upon cell morphology and cell death was assessed using imaging and flow cytometry, respectively. The efficacy of the lead compound was also assessed in a patient-derived explant model.</p><p><strong>Results: </strong>The compounds were found to inhibit prostate cancer proliferation and motility, promote G2/M arrest, multinucleation and apoptosis. Importantly, treatment of patient-derived explants with the lead compound DJ160 demonstrated that the molecule inhibits prostate cancer proliferation, even in samples that appear to be resistant to enzalutamide.</p><p><strong>Conclusions: </strong>Thieno[2,3-<i>b</i>]pyridines therefore represent a potential therapy for prostate cancer, even when current therapies have failed.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e240082"},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of bowel ischemia in patients with mesenteric neuroendocrine tumors after treatment with ¹⁷⁷Lu-DOTATATE.","authors":"Eleonora Pelle, Taymeyah Al-Toubah, Ghassan El-Haddad, Brian Morse, Bhavana Konda, Vineeth Sukrithan, Jonathan Strosberg","doi":"10.1530/EO-25-0033","DOIUrl":"https://doi.org/10.1530/EO-25-0033","url":null,"abstract":"<p><strong>Background: </strong>Lutetium-177 (¹⁷⁷Lu)-DOTATATE is an effective treatment for metastatic gastroenteropancreatic (GEP) NETs. However, radiation can cause transient inflammation/swelling of tumors, which can result in toxicity. Treatment-related small bowel obstruction associated with mesenteric or peritoneal disease has been described. We investigated the potential for intestinal ischemia in ¹⁷⁷Lu-DOTATATE-treated patients.</p><p><strong>Methods: </strong>Clinical records were reviewed of patients with midgut NETs treated with ¹⁷⁷Lu-DOTATATE at the Moffitt Cancer Center between April 2018 and December 2022 and at The Ohio State University between December 2017 and October 2020.</p><p><strong>Results: </strong>Among the cases reviewed, we identified three patients who developed bowel ischemia/perforation shortly after their initial treatment with ¹⁷⁷Lu-DOTATATE. All patients had metastatic small bowel NET with prominent mesenteric mass encasing/obstructing the mesenteric vessels and preexisting symptoms of postprandial abdominal pain.</p><p><strong>Conclusion: </strong>Acute bowel ischemia may be a rare complication of PRRT in patients with mesenteric arterial or venous obstruction from mesenteric metastasis.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e250033"},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIADH as an uncommon presentation of olfactory neuroblastoma: a case-based overview.","authors":"Solene Papart, Adrian F Daly, Elettra Bianchi, Alexandre Jadoul, Gilles Reuter, Olivier Bouchain, Patrick Pétrossians, Albert Beckers","doi":"10.1530/EO-25-0021","DOIUrl":"https://doi.org/10.1530/EO-25-0021","url":null,"abstract":"<p><strong>Background: </strong>Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumour that usually arises in the nasal cavity, typically presenting with unilateral nasal obstruction and epistaxis. In rare instances, ONB can manifest as a paraneoplastic syndrome of inappropriate antidiuretic hormone (SIADH) secretion, leading to hyponatraemia.</p><p><strong>Case presentation: </strong>We describe a 42-year-old woman with a 4-year history of cyclical, symptomatic hyponatraemia characterised by intermittent episodes of dizziness, severe headaches and marked fatigue, initially without overt nasal or otolaryngological symptoms. Investigations confirmed SIADH, yet repeated imaging (including thoracic CT and FDG PET-CT) failed to identify a source. Eventually, a ⁶⁸Ga-DOTANOC PET-CT revealed an isolated lesion in the left ethmoid region. Surgical resection via an endoscopic approach confirmed the diagnosis of a Hyams grade 1 ONB. Following complete tumour removal, the patient's hyponatraemia resolved.</p><p><strong>Literature review: </strong>ONB accounts for <3% of nasal tumours and can present with non-specific symptoms, delaying diagnosis. Most patients have a typical combination of nasal obstruction and epistaxis, but paraneoplastic SIADH is reported in about 2% of cases. Complete surgical excision is the cornerstone of therapy, often accompanied by radiotherapy or chemotherapy for higher-grade lesions. Recent advances suggest that somatostatin receptor imaging and targeted radionuclide therapy might benefit select patients, particularly those with unresectable or recurrent disease.</p><p><strong>Conclusion: </strong>This case highlights the importance of considering ONB in patients with unexplained SIADH, especially when initial investigations are inconclusive. It also underscores the utility of ⁶⁸Ga-DOTANOC PET-CT in detecting occult neuroendocrine tumours, and reinforces the value of prompt surgical intervention for definitive treatment.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e250021"},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12242914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adrenal crisis due to pembrolizumab-induced hypophysitis in a patient with triple-negative breast cancer.","authors":"Sobrina S Mohammed, Sallam Alrosan, Reda Asad","doi":"10.1530/EO-25-0046","DOIUrl":"10.1530/EO-25-0046","url":null,"abstract":"<p><p>We report a case of a 43-year-old woman with stage IIB triple-negative breast cancer (TNBC) on neoadjuvant pembrolizumab presenting in adrenal crisis. Biochemical evaluation revealed isolated adrenocorticotropic hormone (ACTH) deficiency, and MRI demonstrated a partial empty sella; findings consistent with pembrolizumab-induced hypophysitis. Glucocorticoid replacement therapy led to symptom resolution. Pembrolizumab-induced hypophysitis is rare (incidence ∼0.98%), often associated with isolated ACTH deficiency, making diagnosis challenging due to nonspecific symptoms and frequently unremarkable pituitary imaging. As ICI use expands, clinician awareness of immune-related adverse effects (irAEs) is essential to prevent life-threatening complications and improve outcomes.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e250046"},"PeriodicalIF":0.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144531392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world lenvatinib use in metastatic thyroid cancer: early dose intensity and side effect profile in an Australian centre.","authors":"Monica Majumder, Shejil Kumar, Tony Lian, Venessa H M Tsang, Meredith Oatley, Lyndal Tacon, Bruce G Robinson, Anthony Glover, Roderick J Clifton-Bligh, Matti L Gild","doi":"10.1530/EO-24-0062","DOIUrl":"10.1530/EO-24-0062","url":null,"abstract":"<p><strong>Objective: </strong>Lenvatinib is a multi-kinase inhibitor approved in radioiodine-refractory thyroid cancer based on results of a phase III trial. Real-world data have emphasised concerns regarding tolerability of the starting dose (24 mg/day) and frequency of dose-limiting treatment-related adverse effects (TRAEs). We aimed to assess early dose intensity, tolerability and efficacy using lenvatinib in metastatic thyroid cancer patients in an Australian centre.</p><p><strong>Design/methods: </strong>Retrospective medical record review was conducted of patients with advanced/metastatic differentiated, medullary and anaplastic thyroid cancer on lenvatinib at a quaternary referral centre (2014-2023).</p><p><strong>Results: </strong>64 patients were included. Median age at lenvatinib commencement was 67 years (range 38-92). 53% were female. The most common non-nodal metastases were pulmonary (86.4%) and skeletal (50.8%). Most patients commenced lenvatinib at 24 mg/day (48/53; 90.5%), with fewer than half maintaining this dose by 8 weeks (21/45; 46.7%). Those who maintained the 24 mg dose at 8 weeks were younger at lenvatinib commencement (62 years vs 71 years, <i>P</i> = 0.016) and more likely to have poorly differentiated or anaplastic thyroid cancer (42 vs 22%, <i>P</i> = 0.018). During the median 12-month follow-up, the most common TRAEs included hypertension (<i>n</i> = 37), fatigue (<i>n</i> = 35), and nausea (<i>n</i> = 18). In a subgroup of 21/35 patients with differentiated thyroid cancer, median baseline and nadir serum thyroglobulin were 305 and 21.7 μg/L (median reduction 92.5% (IQR 81.1-98.0%)). In 19/35 patients with radiological response data, the majority experienced disease control as best structural response (17/19; 93.2%).</p><p><strong>Conclusion: </strong>This real-world analysis demonstrates difficulties in maintaining early lenvatinib dose intensity, with frequent TRAEs. Greater emphasis on supportive care is needed to maximise early dose intensity and efficacy.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e240062"},"PeriodicalIF":0.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Malignant transformation of parathyromatosis to parathyroid carcinoma with invasive growth and distant metastasis.","authors":"Chittari Venkata Harinarayan, Anugnya Premdas Ranjoalkar, Anisha Sawkar Tandon, Honey Ashok, Madhu Prashant","doi":"10.1530/EO-25-0024","DOIUrl":"10.1530/EO-25-0024","url":null,"abstract":"<p><p>Parathyroid carcinoma (PC) is a rare endocrine malignancy. It accounts for about 1% of all primary hyperparathyroidism (PHPT) cases and 0.005% of all malignancies. PC presents with severe hypercalcemia, often refractory to standard medical treatment, which is crucial for improving patient outcomes. Differentiating PC from atypical parathyroid adenomas and parathyromatosis can be challenging. PC is diagnosed by angio-invasion, lymphatic and perineural invasion, and local malignant invasion with regional and distant metastasis. CD31 positivity on immunohistochemistry, indicating tumor cells within blood vessels in the pseudocapsule (vascular invasion), and a Ki-67% proliferative index of 8% confirm the diagnosis. We describe a 67-year-old man who presented with neck swelling, abdominal pain, and weight loss. Five years prior, he underwent a left inferior parathyroidectomy for a mass, which histological examination identified as clear cell parathyroid adenoma. Three years post-parathyroidectomy, he developed recurrent left-sided neck swelling. Magnetic resonance imaging revealed a lesion with mediastinal extension but no lymph node metastasis. During surgery, the lesion was adherent to the common carotid artery, and histopathological examination confirmed parathyromatosis. Recently, he presented again with new-onset neck swelling, abdominal pain, and weight loss. Biochemical investigations confirmed primary hyperparathyroidism. Invasive growth into surrounding tissues, blood vessels, and nerves, along with lymph node involvement and lung metastasis, with histopathology showing CD31 positivity and a Ki-67% proliferative index of 8%, confirmed the diagnosis of PC. As the tumor was inoperable, hypercalcemia was managed with cinacalcet, resulting in a decline in serum calcium levels.</p><p><strong>Learning points: </strong>Parathyroid carcinoma is one of the rarest malignancies.Parathyromatosis is parathyroid tissue displaced in the neck and mediastinum due to prior surgery or aberrant embryonic development.The diagnosis of parathyroid carcinoma on histopathology is based on:Local invasion into adjacent structures, such as adipose tissues/skeletal muscle bundles.Loco-regional invasion-lymphatic (D240 IHC+), angio-invasion (CD31 IHC+), and perineural invasion.Nuclear pleomorphism, hyperchromatic nuclei, and increased mitosis (high Ki-67 proliferative index of >5%).Regional and distant metastasis in the lungs and other organs.Management of severe hypercalcemia is crucial for improving patient outcomes.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e250024"},"PeriodicalIF":0.0,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radioembolization for neuroendocrine tumors: procedure, application and clinical outcomes.","authors":"Li Shen Ho, Tarik Baetens, Marnix G E H Lam, Arthur J A T Braat","doi":"10.1530/EO-24-0053","DOIUrl":"10.1530/EO-24-0053","url":null,"abstract":"<p><p>Neuroendocrine liver metastases significantly affect patient prognosis and quality of life due to their symptomatic burden and challenging management. Besides conventional systemic therapies, liver-directed therapies improve patient outcomes in patients with liver-dominant disease. These liver-directed therapies have gained interest over the past decade, but their placement in the treatment algorithm of neuroendocrine liver metastases remains largely unclear. The purpose of this review is to evaluate the current role of selective internal radiation therapy (radioembolization) as a treatment for neuroendocrine liver metastases. This review examines the patient selection, procedural aspects, applications, and clinical outcomes. Radioembolization is effective as a standalone treatment. This treatment achieves disease control rates exceeding 90% and improves symptoms and quality of life. Moreover, combining radioembolization with systemic therapies may provide improved treatment response and additional benefits, but further investigation is required. The treatments effectiveness is influenced by appropriate patient selection, including consideration of liver function, tumor vascularity and previous interventions. A multidisciplinary approach is essential in assessing treatment eligibility. Patient management should be tailored on an individual level to optimize outcomes. The incidence of complications is rare (<1%), with radiation-induced liver disease being the most concerning. This review underscores the need for continued research to better understand the optimal use of radioembolization. Specifically, its placement within treatment, particularly in combination with other therapies, requires further exploration, ultimately to improve survival and quality of life for patients with neuroendocrine liver metastases.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e240053"},"PeriodicalIF":0.0,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of a <i>GNAS</i> variant linked to cortisol-producing adrenocortical adenoma.","authors":"Aqfan Jamaluddin, Rachael Wyatt, Andreea Pasaliu, Oliver Ruggles, Davide Calebiro, Caroline M Gorvin, Cristina L Ronchi","doi":"10.1530/EO-25-0009","DOIUrl":"10.1530/EO-25-0009","url":null,"abstract":"<p><strong>Objective: </strong>Adrenocortical adenomas are frequent in the general population and can be associated with autonomous cortisol excess, increasing morbidity and mortality. Altered cAMP/PKA signalling is common in sporadic cortisol-producing adenomas, typically due to somatic activating mutations in the catalytic subunit α of PKA (<i>PRKACA</i>) or the G-protein α subunit, Gα_s (<i>GNAS</i>), which activate cAMP signalling. We previously identified a novel p.Lys58Gln <i>GNAS</i> somatic variant in a patient with a 5.3 cm adenoma and overt Cushing's syndrome. This novel mutation was not charactersised before but provided enough evidence to warrant further investigation.</p><p><strong>Design and methods: </strong>Using HEK293 cells depleted of <i>GNAS</i>, we established wild-type (WT) Gα_s and Gα_s-Lys58Gln stable cell lines and evaluated adrenocorticotropic hormone (ACTH) receptor signalling using a cAMP GloSensor assay, measured CREB transcription factor phosphorylation (pCREB) by AlphaLISA and assessed <i>CRE</i> luciferase reporter activity. Cell viability and apoptosis were also assessed over 5 days.</p><p><strong>Results: </strong>The Gα_s-Lys58Gln variant showed a significantly higher basal cAMP, pCREB and <i>CRE</i> luciferase reporter concentration and a greater response to ACTH (0-10 nM, <i>P</i> < 0.001) compared to WT Gα_s. The variant had no effect on ligand potency. There was also significantly enhanced cell viability and apoptosis in cells with the Gα_s-Lys58Gln variant.</p><p><strong>Conclusions: </strong>In conclusion, our study demonstrated that the Gα_s-Lys58Gln variant is associated with constitutive activation of GNAS signalling, similar to Arg201 mutations previously reported in adrenocortical adenomas, potentially representing a new pathogenic mechanism in a subset of patients with adrenal Cushing syndrome. This variant may also affect cell proliferation and requires further study.</p>","PeriodicalId":72907,"journal":{"name":"Endocrine oncology (Bristol, England)","volume":"5 1","pages":"e250009"},"PeriodicalIF":0.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}