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Åkerström, Tobias
Publications (10 of 10) Show all publications
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.
Open this publication in new window or tab >>Activating mutations in CTNNB1 in aldosterone producing adenomas
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 19546Article in journal (Refereed) 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.

National Category
Endocrinology and Diabetes Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-277306 (URN)10.1038/srep19546 (DOI)000368736400001 ()26815163 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2017-11-30Bibliographically approved
Åkerström, T. (2016). Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Genetic Alterations and Molecular Signatures in Aldosterone Producing Adenomas
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary Aldosteronism (PA) is caused by autonomous overproduction of aldosterone. Aldosterone is necessary for fluid and ion homeostasis. Aberrant overproduction leads to hypertension and cardiovascular damage. With a prevalence of over 5% in the worlds’ hypertensive community, and with over a billion people worldwide having high blood pressure, PA represents a major contributor to health care costs and morbidity. Importantly, 30% of PA patients have a unilateral dominant secretion, an aldosterone producing adenoma (APA), making it possible to cure a substantial portion of patients with surgery. Unfortunately, there is a large underdiagnosis of PA, leading to delayed diagnosis in many patients, worsening their outcome after surgery. A need for better screening techniques, raised awareness and treatment options for PA is warranted.

Since 2011, the genetic understanding of APAs has revolutionized. Somatic mutations turning on an autonomous aldosterone production has been observed in up to 80% of tumors. In this thesis we have investigated the genetic landscape and phenotypes of APAs. By international collaborations we have collected one of the largest cohorts of APAs ever sequenced. We have confirmed and extended the understanding of KCNJ5 mutations, its associated phenotype and the specificity for APAs. We have confirmed a high rate of mutations in ATP1A1, ATP2B3 and CACNA1D, and noted distinct clinical and molecular phenotypes in these tumors. We describe a marker of Zona Glomerulosa cells, perhaps important for the normal regulation and function of these cells. We observe somatic mutations in CTNNB1, occurring in a mutually exclusive manner to the other mutations. Using in situ sequencing, we note genetic heterogeneity in APAs with KCNJ5 mutations. Finally, we evaluate intratumoral aldosterone measurement on a large cohort of tumors, validating a high specificity for APAs. Noting also a difference in the level of intratumoral aldosterone between APAs and a possible association with genotype. Remarkably, we also note a robust correlation between the intracellular concentrations and plasma-aldosterone. We hope that with gained knowledge of the genetic background, the understanding of both pathologic and normal states of the adrenals will increase, and hopefully benefit patients in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 49
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1197
Keywords
Aldosterone, aldosterone producing adenoma, KCNJ5, ATP1A1, ATP2B3, CACNA1D, CTNNB1
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-281042 (URN)978-91-554-9517-6 (ISBN)
Public defence
2016-05-07, Robergssalen, Akademiska sjukhuset, ingång 40, plan 4, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2016-04-15 Created: 2016-03-16 Last updated: 2016-04-21
Åkerström, T., Carling, T., Beuschlein, F. & Hellman, P. (2016). Genetics of adrenocortical tumours. Paper presented at ymposium on New Genetics with Impact on Treatment of Endocrine Tumour Disease, Uppsala, SWEDEN, JUN 04-05, 2015. Journal of Internal Medicine, 280(6), 540-550
Open this publication in new window or tab >>Genetics of adrenocortical tumours
2016 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, no 6, p. 540-550Article in journal (Refereed) Published
Abstract [en]

The recently available genomic sequencing techniques have led to breakthroughs in understanding of the underlying genetic mechanisms in adrenocortical tumours. Disease-causing mutations have been described for aldosterone-producing adenomas, cortisol-producing adenomas and adrenocortical carcinomas. Further, knowledge gained from transcriptome analyses and methylation arrays has provided new insights into the development of these tumours. Elucidation of the genomic landscape of adrenocortical tumours and improved techniques may in the future be useful for early diagnosis through the detection of mutated DNA in the circulation. Moreover, compounds that bind specifically to altered proteins may be used as screening targets or therapeutic agents. Regulation of cortisol release by interaction with an altered subunit in adenylate cyclase may be more complex, but may provide a new option for regulating steroid release. Information about derangements in adrenocortical carcinoma is already helpful for determining patient prognosis. With further knowledge, we may be able to identify novel biomarkers that effectively and noninvasively help in differentiating between benign and malignant disease. It is clear that the next few years will provide much novel information that hopefully will aid in the treatment of patients with adrenocortical tumours.

Keywords
Adrenal tumours, genetics
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-307822 (URN)10.1111/joim.12452 (DOI)000388573300002 ()27864864 (PubMedID)
Conference
ymposium on New Genetics with Impact on Treatment of Endocrine Tumour Disease, Uppsala, SWEDEN, JUN 04-05, 2015
Available from: 2016-11-22 Created: 2016-11-22 Last updated: 2017-11-29Bibliographically approved
Åkerström, T., Willenberg, H. S., Cupisti, K., Ip, J., Backman, S., Moser, A., . . . Hellman, P. (2015). Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.. Endocrine-Related Cancer, 22(5), 735-744
Open this publication in new window or tab >>Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
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2015 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 5, p. 735-744Article in journal (Refereed) Published
Abstract [en]

Aldosterone-producing adenomas (APAs) are found in 1.5-3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca(2) (+) regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca(2) (+) levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

Keywords
ATP1A1; CACNA1D; KCNJ5; primary aldosteronism; aldosterone-producing adenoma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-266639 (URN)10.1530/ERC-15-0321 (DOI)000364022400010 ()26285814 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2015-11-10 Created: 2015-11-10 Last updated: 2017-12-01
Crona, J., Gustavsson, T., Norlén, O., Edfeldt, K., Åkerström, T., Westin, G., . . . Stålberg, P. (2015). Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors.. Annals of Surgical Oncology
Open this publication in new window or tab >>Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors.
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2015 (English)In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene.

METHODS: This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors.

RESULTS: Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found.

CONCLUSION: This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-266643 (URN)10.1245/s10434-014-4351-9 (DOI)25586243 (PubMedID)
Available from: 2015-11-10 Created: 2015-11-10 Last updated: 2017-12-01
Åkerström, T. (2014). Genetic Alterations in Aldosterone Producing Adenomas. (Licentiate dissertation). Uppsala: Uppsala University, Department of Surgical Sciences
Open this publication in new window or tab >>Genetic Alterations in Aldosterone Producing Adenomas
2014 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Uppsala: Uppsala University, Department of Surgical Sciences, 2014. p. 67
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-219929 (URN)
Presentation
2014-03-21, 13:15 (English)
Opponent
Supervisors
Available from: 2014-03-10 Created: 2014-03-07 Last updated: 2014-07-24Bibliographically approved
Hellman, P., Åkerström, T. & Björklund, P. (2014). Molecular derangements in primary aldosteronism. In: Primary Aldosteronism: Molecular Genetics, Endocrinology, and Translational Medicine (pp. 45-52). New York: Springer
Open this publication in new window or tab >>Molecular derangements in primary aldosteronism
2014 (English)In: Primary Aldosteronism: Molecular Genetics, Endocrinology, and Translational Medicine, New York: Springer, 2014, p. 45-52Chapter in book (Refereed)
Place, publisher, year, edition, pages
New York: Springer, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-267999 (URN)
Available from: 2015-12-01 Created: 2015-12-01 Last updated: 2016-12-21
Åkerström, T., Crona, J., Verdugo, A. D., Starker, L. F., Cupisti, K., Willenberg, H. S., . . . Björklund, P. (2012). Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter. PLoS ONE, 7(7), e41926
Open this publication in new window or tab >>Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41926-Article in journal (Refereed) Published
Abstract [en]

Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.

Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p < 0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p < 0.005).

Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183242 (URN)10.1371/journal.pone.0041926 (DOI)000306950200128 ()
Available from: 2012-10-25 Created: 2012-10-23 Last updated: 2017-12-07Bibliographically approved
Staaf, J., Åkerström, T., Ljungström, V., Larsson, S., Karlsson, T., Skogseid, B. & Bergsten, P. (2012). Hög tid att söka till nya MD/PhD-programmet vid Uppsala universitet: Tidig bro mellan preklinisk forskning och klinik. Läkartidningen, 109(17-18), 898-898
Open this publication in new window or tab >>Hög tid att söka till nya MD/PhD-programmet vid Uppsala universitet: Tidig bro mellan preklinisk forskning och klinik
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2012 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 17-18, p. 898-898Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-187488 (URN)22642061 (PubMedID)
Available from: 2012-12-06 Created: 2012-12-06 Last updated: 2017-12-07Bibliographically approved
Åkerström, T., Azizan, E. A., Maharjan, R., Willenberg, H. S., Cupisti, K., Ip, J., . . . Björklund, P.Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas.
Open this publication in new window or tab >>Activating Mutations in CTNNB1 in Aldosterone Producing Adenomas
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(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-218662 (URN)
Available from: 2014-02-13 Created: 2014-02-13 Last updated: 2015-06-26Bibliographically approved
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