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Hellman, P., Björklund, P. & Åkerström, T. (2019). Aldosterone-Producing Adenomas. In: Litwack, Gerald (Ed.), ALDOSTERONE: (pp. 407-431). ELSEVIER ACADEMIC PRESS INC
Öppna denna publikation i ny flik eller fönster >>Aldosterone-Producing Adenomas
2019 (Engelska)Ingår i: ALDOSTERONE / [ed] Litwack, Gerald, ELSEVIER ACADEMIC PRESS INC , 2019, s. 407-431Kapitel i bok, del av antologi (Refereegranskat)
Abstract [en]

Aldosterone-producing adenomas (APA) are more common than initially anticipated. APA cause primary aldosteronism (PA), which affect 3-10% of the hypertensive population. Research during recent years has led to an increased knowledge of the background dysregulation of the increased aldosterone release, where mutation in the gene encoding the potassium channel GIRK4-KCNJ5-is the most common. Moreover, the discovery of aldosterone-producing cell clusters in apparently normal adenomas has also led to increased understanding of the development of PA, and presumably also APA. A continuum ranging from low-renin hypertension to APA and overt PA is reasoned, and the secondary effects of aldosterone on especially the cardiovascular system have also become more evident. Diagnostics of PA and APA is important in order to reduce cardiovascular morbidity and mortality, but the diagnostic methods are somewhat unspecific and insensitive, indicating the need for novel methods.

Ort, förlag, år, upplaga, sidor
ELSEVIER ACADEMIC PRESS INC, 2019
Serie
Vitamins and Hormones, ISSN 0083-6729 ; 109
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-401949 (URN)10.1016/bs.vh.2018.10.007 (DOI)000500344300018 ()30678866 (PubMedID)978-0-12-817782-2 (ISBN)
Tillgänglig från: 2020-01-10 Skapad: 2020-01-10 Senast uppdaterad: 2020-01-10Bibliografiskt granskad
Backman, S., Åkerström, T., Maharjan, R., Cupisti, K., Willenberg, H. S., Hellman, P. & Björklund, P. (2019). RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas. Scientific Reports, 9, Article ID 6269.
Öppna denna publikation i ny flik eller fönster >>RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
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2019 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 6269Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.

Ort, förlag, år, upplaga, sidor
NATURE PUBLISHING GROUP, 2019
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-383193 (URN)10.1038/s41598-019-41525-2 (DOI)000465001600023 ()31000732 (PubMedID)
Forskningsfinansiär
VetenskapsrådetKnut och Alice Wallenbergs Stiftelse
Anmärkning

De två första författarna delar förstaförfattarskapet.

Tillgänglig från: 2019-07-24 Skapad: 2019-07-24 Senast uppdaterad: 2019-07-24Bibliografiskt granskad
Maharjan, R., Backman, S., Åkerström, T., Hellman, P. & Björklund, P. (2018). Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival. Scientific Reports, 8, Article ID 8610.
Öppna denna publikation i ny flik eller fönster >>Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival
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2018 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 8610Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The Wnt/β-Catenin signaling pathway is one of the most frequently altered pathways in adrenocortical carcinomas (ACCs). The aim of this study was to investigate the status of Wnt/β-Catenin signaling pathway by analyzing the expression level of β-Catenin and the mutational status of APC, AXIN2, CTNNB1, and ZNRF3 in ACCs. Mutations in APC, CTNNB1, ZNRF3 and homozygous deletions in ZNRF3 were observed in 3.8% (2/52), 11.5% (6/52), 1.9% (1/52) and 17.3% (9/52) of the cohort respectively. Novel interstitial deletions in CTNNB1 spanning intron 1 to exon 3/intron 3 were also found in 7.7% (4/52) of the tumours. All the observed alterations were mutually exclusive. Nuclear accumulation of β-Catenin, increased expression of Cyclin D1 and significantly higher expression of AXIN2 (p = 0.0039), ZNRF3 (p = 0.0032) and LEF1(p = 0.0090) observed in the tumours harbouring the deletion in comparison to tumours without CTNNB1 mutation demonstrates that the truncated β-Catenin is functionally active and erroneously activates the downstream targets. Significantly lower overall survival rate in patients with tumours harbouring alterations in APC/CTNNB1/ZNRF3 in comparison to those without mutation was observed. In conclusion, the discovery of novel large deletions in addition to the point mutations in CTNNB1 infers that activation of Wnt/β-Catenin pathway via alterations in CTNNB1 occurs frequently in ACCs. We also confirm that alterations in Wnt/β-Catenin signaling pathway members have a negative effect on overall survival of patients.

Nyckelord
adrenocortical carcinomas, CTNNB1, mutation, β-Catenin, survival
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi Medicin och hälsovetenskap
Forskningsämne
Molekylär genetik; Endokrinologi och Diabetologi
Identifikatorer
urn:nbn:se:uu:diva-325980 (URN)10.1038/s41598-018-26799-2 (DOI)000434122600035 ()29872083 (PubMedID)
Forskningsfinansiär
CancerfondenVetenskapsrådetKnut och Alice Wallenbergs Stiftelse
Tillgänglig från: 2017-07-03 Skapad: 2017-07-03 Senast uppdaterad: 2018-11-12Bibliografiskt granskad
Björklund, P. & Backman, S. (2018). Epigenetics of pheochromocytoma and paraganglioma. Molecular and Cellular Endocrinology, 469, 92-97
Öppna denna publikation i ny flik eller fönster >>Epigenetics of pheochromocytoma and paraganglioma
2018 (Engelska)Ingår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 469, s. 92-97Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising in the medullae of the adrenal glands or in paraganglia. The knowledge of the tumor biology of these lesions has increased dramatically during the past two decades and more than a dozen recurrently mutated genes have been identified. Different clusters have been described that share epigenetic signatures. Mutations in the succinate dehydrogenase complex subunit genes play a pivotal role in reprogramming the epigenetic state of these tumors by inhibiting epigenetic regulators such as TET enzymes and histone demethylases. Another subgroup of tumors carries hypomethylated genomes, and overexpression of several microRNAs has been described. While much remains to be investigated regarding the epigenetics of PPGLs, it is clear that it plays an important role in PPGL biology.

Ort, förlag, år, upplaga, sidor
ELSEVIER IRELAND LTD, 2018
Nyckelord
Pheochromocytoma, Paraganglioma, Epigenetics, Adrenal, Methylation
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:uu:diva-369529 (URN)10.1016/j.mce.2017.06.016 (DOI)000447949400012 ()28630023 (PubMedID)
Forskningsfinansiär
Cancerfonden, 15 0130Erik, Karin och Gösta Selanders stiftelse
Tillgänglig från: 2018-12-19 Skapad: 2018-12-19 Senast uppdaterad: 2018-12-19Bibliografiskt granskad
Dumanski, J. P., Rasi, C., Björklund, P., Davies, H., Ali, A. S., Grönberg, M., . . . Tiensuu Janson, E. (2017). A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. Endocrine-Related Cancer, 24(8), 427-443
Öppna denna publikation i ny flik eller fönster >>A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
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2017 (Engelska)Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, nr 8, s. 427-443Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

Nyckelord
DNA excision-repair pathway, cancer predisposition, familial cancer, oxidative stress, small intestinal carcinoid
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:uu:diva-328686 (URN)10.1530/ERC-17-0196 (DOI)000406493000011 ()28634180 (PubMedID)
Tillgänglig från: 2017-08-29 Skapad: 2017-08-29 Senast uppdaterad: 2019-02-07Bibliografiskt granskad
Backman, S., Maharjan, R., Falk Delgado, A., Crona, J., Cupisti, K., Stålberg, P., . . . Björklund, P. (2017). Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations. Scientific Reports, 7, Article ID 44943.
Öppna denna publikation i ny flik eller fönster >>Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
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2017 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 44943Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.

Nationell ämneskategori
Cancer och onkologi Kirurgi
Identifikatorer
urn:nbn:se:uu:diva-320646 (URN)10.1038/srep44943 (DOI)000397026500001 ()28327598 (PubMedID)
Tillgänglig från: 2017-06-30 Skapad: 2017-06-30 Senast uppdaterad: 2019-10-30Bibliografiskt granskad
Smith-Anttila, C. J. A., Bensing, S., Alimohammadi, M., Dalin, F., Oscarson, M., Zhang, M.-D., . . . Kämpe, O. (2017). Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1. Autoimmunity, 50(4), 223-231
Öppna denna publikation i ny flik eller fönster >>Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1
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2017 (Engelska)Ingår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, nr 4, s. 223-231Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

Nyckelord
APS1, endothelin-converting enzyme-2, ECE-2, pituitary autoantibodies, pancreas
Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:uu:diva-333619 (URN)10.1080/08916934.2017.1332183 (DOI)000407564500005 ()28557628 (PubMedID)
Tillgänglig från: 2017-11-16 Skapad: 2017-11-16 Senast uppdaterad: 2017-11-16Bibliografiskt granskad
Åkerström, T., Maharjan, R., Willenberg, H. S., Cupisti, K., Ip, J., Moser, A., . . . Björklund, P. (2016). Activating mutations in CTNNB1 in aldosterone producing adenomas. Scientific Reports, 6, Article ID 19546.
Öppna denna publikation i ny flik eller fönster >>Activating mutations in CTNNB1 in aldosterone producing adenomas
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2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 19546Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Primary aldosteronism (PA) is the most common cause of secondary hypertension with a prevalenceof 5–10% in unreferred hypertensive patients. Aldosterone producing adenomas (APAs) constitutea large proportion of PA cases and represent a surgically correctable form of the disease. The WNTsignaling pathway is activated in APAs. In other tumors, a frequent cause of aberrant WNT signaling ismutation in the CTNNB1 gene coding for β-catenin. Our objective was to screen for CTNNB1 mutationsin a well-characterized cohort of 198 APAs. Somatic CTNNB1 mutations were detected in 5.1% of thetumors, occurring mutually exclusive from mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D. Allof the observed mutations altered serine/threonine residues in the GSK3β binding domain in exon 3.The mutations were associated with stabilized β-catenin and increased AXIN2 expression, suggestingactivation of WNT signaling. By CYP11B2 mRNA expression, CYP11B2 protein expression, and directmeasurement of aldosterone in tumor tissue, we confirmed the ability for aldosterone production. Thisreport provides compelling evidence that aberrant WNT signaling caused by mutations in CTNNB1 occurin APAs. This also suggests that other mechanisms that constitutively activate the WNT pathway maybe important in APA formation.

Nationell ämneskategori
Endokrinologi och diabetes Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-277306 (URN)10.1038/srep19546 (DOI)000368736400001 ()26815163 (PubMedID)
Forskningsfinansiär
CancerfondenVetenskapsrådet
Tillgänglig från: 2016-02-19 Skapad: 2016-02-19 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
Crona, J., Backman, S., Kugelberg, J., Maharjan, R., Björklund, P. & Hellman, P. (2016). Multiregion Analysis Reveal Evolutionary Patterns and a Chromosomal Instability Signature in Pancreatic Neuroendocrine Tumours. In: : . Paper presented at 13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 09-11, 2016, Barcelona, SPAIN (pp. 6-6). , 103
Öppna denna publikation i ny flik eller fönster >>Multiregion Analysis Reveal Evolutionary Patterns and a Chromosomal Instability Signature in Pancreatic Neuroendocrine Tumours
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2016 (Engelska)Konferensbidrag, Publicerat paper (Refereegranskat)
Nyckelord
Cancer evolution, Molecular genetics, Neuroendocrine tumor
Nationell ämneskategori
Cancer och onkologi Endokrinologi och diabetes Neurologi
Identifikatorer
urn:nbn:se:uu:diva-313700 (URN)000386481600015 ()
Konferens
13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 09-11, 2016, Barcelona, SPAIN
Tillgänglig från: 2017-01-23 Skapad: 2017-01-23 Senast uppdaterad: 2019-10-30
Björklund, P., Pacak, K. & Crona, J. (2016). Precision medicine in pheochromocytoma and paraganglioma: current and future concepts. Paper presented at Symposium on New Genetics with Impact on Treatment of Endocrine Tumour Disease, JUN 04-05, 2015, Uppsala, SWEDEN. Journal of Internal Medicine, 286(6), 559-573
Öppna denna publikation i ny flik eller fönster >>Precision medicine in pheochromocytoma and paraganglioma: current and future concepts
2016 (Engelska)Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, nr 6, s. 559-573Artikel i tidskrift, Meeting abstract (Refereegranskat) Published
Abstract [en]

Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.

Nyckelord
cancer metabolism, neuroendocrine tumours, paraganglioma, personalized medicine, pheochromocytoma, precision medicine
Nationell ämneskategori
Kirurgi Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-311489 (URN)10.1111/joim.12507 (DOI)000388573300004 ()27165774 (PubMedID)
Konferens
Symposium on New Genetics with Impact on Treatment of Endocrine Tumour Disease, JUN 04-05, 2015, Uppsala, SWEDEN
Tillgänglig från: 2016-12-29 Skapad: 2016-12-28 Senast uppdaterad: 2019-10-30Bibliografiskt granskad
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