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  • 1.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Bivik Eding, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Franzén, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Konstantinell, Aelita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts2015In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 3, p. 331-343Article in journal (Refereed)
    Abstract [en]

    Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, Pless than0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, P=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, P=0.00041 (cytoplasm), P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

  • 2.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Genetics of primary hyperaldosteronism2016In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 23, no 10, p. R437-R454Article, review/survey (Refereed)
    Abstract [en]

    Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

  • 3.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Brauckhoff, Michael
    Haukeland University Hospital, Bergen; University of Bergen, Norway .
    Walz, Martin
    Klinikum Essen Mitte, Essen, Germany .
    Alesina, Piero
    Klinikum Essen Mitte, Essen, Germany .
    Arnesen, Thomas
    Haukeland University Hospital, Bergen; University of Bergen, Norway.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Complementary somatic mutations of KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 1, p. L1-L4Article in journal (Other academic)
    Abstract [en]

    n/a

  • 4.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Proliferative responses to altered 17β-hydroxysteroid dehydrogenase (17HSD) type 2 expression in human breast cancer cells are dependent on endogenous expression of 17HSD type 1 and the oestradiol receptors2006In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 13, no 3, p. 875-884Article in journal (Refereed)
    Abstract [en]

    The primary source of oestrogen in premenopausal women is the ovary but, after menopause, oestrogen biosynthesis in peripheral tissue is the exclusive site of formation. An enzyme group that affects the availability of active oestrogens is the 17β-hydroxysteroid dehydrogenase (17HSD) family. In breast cancer, 17HSD type 1 and type 2 have been mostly investigated and seem to be the principal 17HSD enzymes involved thus far. The question whether 17HSD type 1 or type 2 is of greatest importance in breast tumour development is still not clear. The aim of this study was to investigate how the loss of 17HSD type 2 expression, using siRNA in the non-tumour breast epithelial cells HMEC (human mammal epithelial cells) and MCF10A, and gain of 17HSD type 2 expression, using transient transfection in the breast cancer derived cell lines MCF7 and T47D, affect oestradiol conversion and proliferation rate measured as S-phase fraction. We further investigated how this was related to the endogenous expression of 17HSD type 1 and oestradiol receptors in the examined cell lines. The oestradiol level in the medium changed significantly in the MCF7 transfected cells and the siRNA-treated HMEC cells, but not in T47D or MCF10A. The S-phase fraction decreased in the 17HSD type 2-transfected MCF7 cells and the siRNA-treated HMEC cells. The results seemed to be dependent on the endogenous expression of 17HSD type 1 and the oestradiol receptors. In conclusion, we found that high or low levels of 17HSD type 2 affected the oestradiol concentration significantly. However, the response was dependent on the endogenous expression of 17HSD type 1. Expression of 17HSD type 1 seems to be dominant to 17HSD type 2. Therefore, it may be important to investigate a ratio between 17HSD type 1 and 17HSD type 2.

  • 5.
    Karger, Stefan
    et al.
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    Weidinger, Carl
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    Krause, Kerstin
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    Sheu, Sien-Yi
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Aigner, Thomas
    Institute of Pathology, University of Leipzig, Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle-Wittenberg, Halle, Germany.
    Schmid, Kurt-Werner
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Dralle, Henning
    Department of Surgery, University of Halle-Wittenberg, Halle, Germany.
    Fuhrer, Dagmar
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    FOXO3a: a novel player in thyroid carcinogenesis?2009In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 16, no 1, p. 189-99Article in journal (Refereed)
    Abstract [en]

    The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H(2)O(2) exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. In vivo, we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.

  • 6.
    Krauss, Tobias
    et al.
    Univ Freiburg, Germany.
    Ferrara, Alfonso Massimiliano
    IRCCS, Italy.
    Links, Thera P.
    Univ Groningen, Netherlands.
    Wellner, Ulrich
    Univ Lubeck, Germany.
    Bancoss, Irina
    Mayo Clin, MN USA.
    Kvachenyuk, Andrey
    NAMS Ukraine, Ukraine.
    Gomez de las Heras, Karim Villar
    Serv Salud Castilla La Mancha SESCAM, Spain.
    Yukina, Marina Y.
    Endocrinol Res Ctr, Russia.
    Petrov, Roman
    Bakhrushin Bros Moscow City Hosp, Russia.
    Bullivant, Garrett
    Univ Hlth Network, Canada.
    von Duecker, Laura
    Albert Ludwigs Univ, Germany.
    Jadhav, Swati
    King Edward Mem Hosp, India.
    Ploeckinger, Ursula
    Charite Univ Med Berlin, Germany.
    Welin, Staffan
    Uppsala Univ Hosp, Sweden.
    Schalin-Jantti, Camilla
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Pfeifer, Marija
    Univ Med Ctr, Slovenia.
    Ngeow, Joanne
    Nanyang Technol Univ, Singapore; Nanyang Technol Univ, Singapore.
    Hasse-Lazar, Kornelia
    MSC Mem Inst, Poland.
    Sanso, Gabriela
    Hosp Ninos Dr Ricardo Gutierrez, Argentina.
    Qi, Xiaoping
    Wenzhou Med Univ, Peoples R China.
    Ugurlu, M. Umit
    Marmara Univ, Turkey.
    Diaz, Rene E.
    Hosp Salvador, Chile.
    Wohllk, Nelson
    Univ Chile, Chile.
    Peczkowska, Mariola
    Inst Cardiol, Poland.
    Aberle, Jens
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Lourenco Jr, Delmar M.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Pereira, Maria A. A.
    Univ Sao Paulo, Brazil.
    Fragoso, Maria C. B. V
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Hoff, Ana O.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Almeida, Madson Q.
    Univ Sao Paulo, Brazil; Univ Sao Paulo, Brazil.
    Violante, Alice H. D.
    Univ Fed Rio de Janeiro, Brazil.
    Ouidute, Ana R. P.
    Fed Univ Ceara UFC, Brazil.
    Zhang, Zhewei
    Zhejiang Univ, Peoples R China.
    Recasens, Monica
    Hosp Univ Girona, Spain.
    Robles Diaz, Luis
    Hosp Univ 12 Octubre, Spain.
    Kunavisarut, Tada
    Mahidol Univ, Thailand.
    Wannachalee, Taweesak
    Mahidol Univ, Thailand.
    Sirinvaravong, Sirinart
    Mahidol Univ, Thailand.
    Jonasch, Eric
    Univ Texas MD Anderson Canc Ctr, TX 77030 USA.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Israel.
    Fraenkel, Merav
    Hadassah Hebrew Univ, Israel.
    Beltsevich, Dmitry
    Endocrinol Res Ctr, Russia.
    Egorov, Viacheslav I
    Bakhrushin Bros Moscow City Hosp, Russia.
    Bausch, Dirk
    Univ Lubeck, Germany.
    Schott, Matthias
    Heinrich Heine Univ, Germany.
    Tiling, Nikolaus
    Charite Univ Med Berlin, Germany.
    Pennelli, Gianmaria
    Univ Padua, Italy.
    Zschiedrich, Stefan
    Albert Ludwigs Univ, Germany.
    Daerr, Roland
    Albert Ludwigs Univ, Germany; Univ Freiburg, Germany.
    Ruf, Juri
    Albert Ludwigs Univ, Germany.
    Denecke, Timm
    Charite Univ Med Berlin, Germany.
    Link, Karl-Heinrich
    Asklepios Paulinen Klin, Germany.
    Zovato, Stefania
    IRCCS, Italy.
    von Dobschuetz, Ernst
    Acad Teaching Hosp Univ Hamburg, Germany.
    Yaremchuk, Svetlana
    NAMS Ukraine, Ukraine.
    Amthauer, Holger
    Charite Univ Med Berlin, Germany.
    Makay, Ozer
    Dept Gen Surg, Turkey.
    Patocs, Attila
    Semmelweis Univ, Hungary; Semmelweis Univ, Hungary.
    Walz, Martin K.
    Huyssens Fdn Clin, Germany.
    Huber, Tobias B.
    Univ Med Ctr Hamburg Eppendorf, Germany.
    Seufert, Jochen
    Univ Freiburg, Germany.
    Hellman, Per
    Uppsala Univ, Sweden.
    Ekaterina, Raymond H.
    Univ Toronto, Canada; Mt Sinai Hosp, Canada.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Schiavi, Francesca
    IRCCS, Italy.
    Malinoc, Angelica
    Albert Ludwigs Univ, Germany.
    Reisch, Nicole
    Ludwigs Maximilians Univ Munich, Germany.
    Jarzab, Barbara
    MSC Mem Inst, Poland.
    Barontini, Marta
    Hosp Ninos Dr Ricardo Gutierrez, Argentina.
    Januszewicz, Andrzej
    Inst Cardiol, Poland.
    Shah, Nalini
    King Edward Mem Hosp, India.
    Young, William F. Jr.
    Mayo Clin, MN USA.
    Opocher, Giuseppe
    Veneto Inst Oncol IOV IRCCS, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs Univ, Germany.
    Bausch, Birke
    Univ Freiburg, Germany.
    Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors2018In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 9, p. 783-793Article in journal (Refereed)
    Abstract [en]

    Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P amp;lt; 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were amp;gt;= 2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off amp;gt;= 2.8 cm, 44% and 91% for TVDT cut-off of amp;lt;= 24 months). In 117 of 273 patients, PanNETs amp;gt; 1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs amp;lt; 2.8 cm vs amp;gt;= 2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

  • 7.
    Neumann, Hartmut P.
    et al.
    Albert Ludwigs Univ, Germany.
    Young, William F. Jr.
    Mayo Clin, NY USA.
    Krauss, Tobias
    Univ Freiburg, Germany.
    Bayley, Jean-Pierre
    Leiden Univ, Netherlands.
    Schiavi, Francesca
    IRCCS, Italy.
    Opocher, Giuseppe
    IRCCS, Italy.
    Boedeker, Carsten C.
    HELIOS Hanseklinikum Stralsund, Germany.
    Tirosh, Amit
    Tel Aviv Univ, Israel.
    Castinetti, Frederic
    Aix Marseille Univ, France; Hop Conception, France.
    Ruf, Juri
    Albert Ludwigs Univ, Germany.
    Beltsevich, Dmitry
    Endocrinol Res Ctr, Russia.
    Walz, Martin
    Kliniken Essen Mitte, Germany; Kliniken Essen Mitte, Germany.
    Groeben, Harald-Thomas
    Kliniken Essen Mitte, Germany.
    von Dobschuetz, Ernst
    Univ Hamburg, Germany.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Wohllk, Nelson
    Univ Chile, Spain.
    Pfeifer, Marija
    Univ Med Ctr Ljubljana, Slovenia.
    Lourenco, Delmar M. Jr.
    Univ Sao Paulo, Brazil.
    Peczkowska, Mariola
    Inst Cardiol, Poland.
    Patocs, Attila
    Hungarian Acad Sci, Hungary; Semmelweis Univ, Hungary.
    Ngeow, Joanne
    Nanyang Technol Univ Singapore, Singapore; Natl Canc Ctr Singapore, Singapore.
    Makay, Ozer
    Ege Univ, Turkey.
    Shah, Nalini S.
    King Edward Mem Hosp, India.
    Tischler, Arthur
    Tufts Med Ctr, MA USA; Tufts Univ, MA 02111 USA.
    Leijon, Helena
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Pennelli, Gianmaria
    Univ Padua, Italy.
    Villar Gomez de las Heras, Karina
    Serv Salud Castilla La Mancha SESCAM, Spain.
    Links, Thera P.
    Univ Groningen, Netherlands.
    Bausch, Birke
    Univ Freiburg, Germany.
    Eng, Charis
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    65 YEARS OF THE DOUBLE HELIX Genetics informs precision practice in the diagnosis and management of pheochromocytoma2018In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 8, p. T201-T219Article, review/survey (Refereed)
    Abstract [en]

    Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with amp;gt;35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

  • 8.
    Welander, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Andreasson, Adam
    Karolinska University Hospital, Sweden.
    Brauckhoff, Michael
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Backdahl, Martin
    Karolinska University Hospital, Sweden.
    Larsson, Catharina
    Karolinska University Hospital, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Frequent EPAS1/HIF2 alpha exons 9 and 12 mutations in non-familial pheochromocytoma2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 3, p. 495-504Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas are neuroendocrine tumors arising from the adrenal medulla. While heritable mutations are frequently described, less is known about the genetics of sporadic pheochromocytoma. Mutations in genes involved in the cellular hypoxia response have been identified in tumors, and recently EPAS1, encoding HIF2 alpha, has been revealed to be a new gene involved in the pathogenesis of pheochromocytoma and abdominal paraganglioma. The aim of this study was to further characterize EPAS1 alterations in non-familial pheochromocytomas. Tumor DNA from 42 adrenal pheochromocytoma cases with apparently sporadic presentation, without known hereditary mutations in predisposing genes, were analyzed for mutations in EPAS1 by sequencing of exons 9 and 12, which contain the two hydroxylation sites involved in HIF2a degradation, and also exon 2. In addition, the copy number at the EPAS1 locus as well as transcriptome-wide gene expression were studied by DNA and RNA microarray analyses, respectively. We identified six missense EPAS1 mutations, three in exon 9 and three in exon 12, in five of 42 pheochromocytomas (12%). The mutations were both somatic and constitutional, and had no overlap in 11 cases (26%) with somatic mutations in NF1 or RET. One sample had two different EPAS1 mutations, shown by cloning to occur in cis, possibly indicating a novel mechanism of HIF2a stabilization through inactivation of both hydroxylation sites. One of the tumors with an EPAS1 mutation also had a gain in DNA copy number at the EPAS1 locus. All EPAS1-mutated tumors displayed a pseudo-hypoxic gene expression pattern, indicating an oncogenic role of the identified mutations.

  • 9.
    Welander, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas2011In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 18, no 6, p. 253-276Article, review/survey (Refereed)
    Abstract [en]

    Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors of the adrenal glands and the sympathetic and parasympathetic paraganglia. They can occur sporadically or as a part of different hereditary tumor syndromes. About 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered. The clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background of the tumors. By reviewing more than 1700 reported cases of hereditary PCC and PGL, a thorough summary of the genetics and clinical features of these tumors is given, both as part of the classical syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease, neurofibromatosis type 1, and succinate dehydrogenase-related PCC-PGL and within syndromes associated with a smaller fraction of PCCs/PGLs, such as Carney triad, Carney-Stratakis syndrome, and MEN1. The review also covers the most recently discovered susceptibility genes including KIF1Bβ, EGLN1/PHD2, SDHAF2, TMEM127, SDHA, and MAX, as well as a comparison with the sporadic form. Further, the latest advances in elucidating the cellular pathways involved in PCC and PGL development are discussed in detail. Finally, an algorithm for genetic testing in patients with PCC and PGL is proposed.

  • 10.
    Welander, Jenny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    The NF1 gene: a frequent mutational target in sporadic pheochromocytomas and beyond2013In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 20, no 4, p. C13-C17Article in journal (Other academic)
    Abstract [en]

    Patients suffering from the neurofibromatosis type 1 syndrome, which is caused by germline mutations in the NF1 gene, have a tiny but not negligible risk of developing pheochromocytomas. It is, therefore, of interest that the NF1 gene has recently been revealed to carry somatic, inactivating mutations in a total of 35 (21.7%) of 161 sporadic pheochromocytomas in two independent tumor series. A majority of the tumors in both studies displayed loss of heterozygosity at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with neurofibromatosis type 1 syndrome-associated pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. A literature and public mutation database review has revealed that pheochromocytomas are among those human neoplasms in which somatic NF1 alterations are most frequent.

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