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Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

ABSTRACT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples.The study was conducted at university hospitals.Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study.Outcomes included genetic screening and clinical characteristics.Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

SUBMITTER: Denes J

PROVIDER: S-EPMC4333031 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

Dénes Judit J Swords Francesca F Rattenberry Eleanor E Stals Karen K Owens Martina M Cranston Treena T Xekouki Paraskevi P Moran Linda L Kumar Ajith A Wassif Christopher C Fersht Naomi N Baldeweg Stephanie E SE Morris Damian D Lightman Stafford S Agha Amar A Rees Aled A Grieve Joan J Powell Michael M Boguszewski Cesar Luiz CL Dutta Pinaki P Thakker Rajesh V RV Srirangalingam Umasuthan U Thompson Chris J CJ Druce Maralyn M Higham Claire C Davis Julian J Eeles Rosalind R Stevenson Mark M O'Sullivan Brendan B Taniere Phillipe P Skordilis Kassiani K Gabrovska Plamena P Barlier Anne A Webb Susan M SM Aulinas Anna A Drake William M WM Bevan John S JS Preda Cristina C Dalantaeva Nadezhda N Ribeiro-Oliveira Antônio A Garcia Isabel Tena IT Yordanova Galina G Iotova Violeta V Evanson Jane J Grossman Ashley B AB Trouillas Jacqueline J Ellard Sian S Stratakis Constantine A CA Maher Eamonn R ER Roncaroli Federico F Korbonits Márta M

The Journal of clinical endocrinology and metabolism 20141212 3

<h4>Context</h4>Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence.<h4>Objective</h4>The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL.<h4>Design</h4>Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, ...[more]

PMID: 25494863

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Project description:BackgroundPheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors that are mostly benign. Metastatic disease does occur in about 10% of cases of PCC and up to 25% of PGL, and for these patients no effective therapies are available. Patients with mutations in the succinate dehydrogenase subunit B (SDHB) gene tend to have metastatic disease. We hypothesized that a down-regulation in the active succinate dehydrogenase B subunit should result in notable changes in cellular metabolic profile and could present a vulnerability point for successful pharmacological targeting.MethodsMetabolomic analysis was performed on human hPheo1 cells and shRNA SDHB knockdown hPheo1 (hPheo1 SDHB KD) cells. Additional analysis of 115 human fresh frozen samples was conducted. In vitro studies using N1,N11-diethylnorspermine (DENSPM) and N1,N12- diethylspermine (DESPM) treatments were carried out. DENSPM efficacy was assessed in human cell line derived mouse xenografts.ResultsComponents of the polyamine pathway were elevated in hPheo1 SDHB KD cells compared to wild-type cells. A similar observation was noted in SDHx PCC/PGLs tissues compared to their non-mutated counterparts. Specifically, spermidine, and spermine were significantly elevated in SDHx-mutated PCC/PGLs, with a similar trend in hPheo1 SDHB KD cells. Polyamine pathway inhibitors DENSPM and DESPM effectively inhibited growth of hPheo1 cells in vitro as well in mouse xenografts.ConclusionsThis study demonstrates overactive polyamine pathway in PCC/PGL with SDHB mutations. Treatment with polyamine pathway inhibitors significantly inhibited hPheo1 cell growth and led to growth suppression in xenograft mice treated with DENSPM. These studies strongly implicate the polyamine pathway in PCC/PGL pathophysiology and provide new foundation for exploring the role for polyamine analogue inhibitors in treating metastatic PCC/PGL. PRéCIS: Cell line metabolomics on hPheo1 cells and PCC/PGL tumor tissue indicate that the polyamine pathway is activated. Polyamine inhibitors in vitro and in vivo demonstrate that polyamine inhibitors are promising for malignant PCC/PGL treatment. However, further research is warranted.

Dataset Information

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

Publications

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

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