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Crona, J., Lamarca, A., Ghosal, S., Welin, S., Skogseid, B. & Pacak, K. (2019). Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocrine-Related Cancer, 26(5), 539-550
Open this publication in new window or tab >>Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis
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2019 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 5, p. 539-550Article, review/survey (Refereed) Published
Abstract [en]

Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients according to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 (95% CI 1.79-18.06)) as well as norepinephrine (OR 3.01 (95% CI 1.02-8.79)) and dopa mine (OR 6.39 (95% CI 1.62-25.24)) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 (95% CI 1.02-1.06)) and metastases (HR 6.13 (95% CI 2.86-13.13)) but neither paraganglioma nor SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD, 2019
Keywords
pheochromocytoma, paraganglioma, molecular genetics, driver mutations, meta-analysis
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-383282 (URN)10.1530/ERC-19-0024 (DOI)000465198700009 ()30893643 (PubMedID)
Available from: 2019-05-14 Created: 2019-05-14 Last updated: 2019-05-14Bibliographically approved
Crona, J., Beuschlein, F., Pacak, K. & Skogseid, B. (2018). Advances in adrenal tumors 2018. Endocrine-Related Cancer, 25(7), R405-R420
Open this publication in new window or tab >>Advances in adrenal tumors 2018
2018 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 7, p. R405-R420Article, review/survey (Refereed) Published
Abstract [en]

This review aims to provide clinicians and researchers with a condensed update on the most important studies in the field during 2017. We present the academic output measured by active clinical trials and peer-reviewed published manuscripts. The most important and contributory manuscripts were summarized for each diagnostic entity, with a particular focus on manuscripts that describe translational research that have the potential to improve clinical care. Finally, we highlight the importance of collaborations in adrenal tumor research, which allowed for these recent advances and provide structures for future success in this scientific field.

Keywords
adrenal tumor, adrenocortical adenoma, adrenocortical carcinoma, paraganglioma, pheochromocytoma
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-363615 (URN)10.1530/ERC-18-0138 (DOI)000438079000002 ()29794126 (PubMedID)
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-11-12Bibliographically approved
Monazzam, A., Lau, J., Velikyan, I., Li, S.-C., Razmara, M., Rosenström, U., . . . Skogseid, B. (2018). Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET. Scientific Reports, 8, Article ID 748.
Open this publication in new window or tab >>Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed) Published
Abstract [en]

Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-342327 (URN)10.1038/s41598-017-18855-0 (DOI)000422637200007 ()29335487 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved
Åkerström, G., Stålberg, P. & Skogseid, B. (2018). Multiple Endocrine Neoplasia type 2. In: Shane Y Morita, Charles M Balch, V. Suzanne Klimberg, Timothy M. Pawlik, Mitchell C. Posner, Kenneth K. Tanabe (Ed.), Textbook of Complex General Surgical Oncology: . McGraw-Hill
Open this publication in new window or tab >>Multiple Endocrine Neoplasia type 2
2018 (English)In: Textbook of Complex General Surgical Oncology / [ed] Shane Y Morita, Charles M Balch, V. Suzanne Klimberg, Timothy M. Pawlik, Mitchell C. Posner, Kenneth K. Tanabe, McGraw-Hill, 2018Chapter in book (Refereed)
Place, publisher, year, edition, pages
McGraw-Hill, 2018
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-308335 (URN)0071793313 (ISBN)
Available from: 2016-11-24 Created: 2016-11-24 Last updated: 2017-10-26Bibliographically approved
Razmara, M., Monazzam, A. & Skogseid, B. (2018). Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration. Cell Communication and Signaling, 16, Article ID 64.
Open this publication in new window or tab >>Reduced menin expression impairs rapamycin effects as evidenced by an increase in mTORC2 signaling and cell migration
2018 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 16, article id 64Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Mammalian target of rapamycin (mTOR) is a master regulator of various cellular responses by forming two functional complexes, mTORC1 and mTORC2. mTOR signaling is frequently dysregulated in pancreatic neuroendocrine tumors (PNETs). mTOR inhibitors have been used in attempts to treat these lesions, and prolonged progression free survival has been recorded. If this holds true also for the multiple endocrine neoplasia type 1 (MEN1) associated PNETs is yet unclear. We investigated the relationship between expression of the MEN1 protein menin and mTOR signaling in the presence or absence of the mTOR inhibitor rapamycin.

METHODS: In addition to use of menin wild type and menin-null mouse embryonic fibroblasts (MEFs), menin was silenced by siRNA in pancreatic neuroendocrine tumor cell line BON-1. Panels of protein phosphorylation, as activation markers downstream of PI3k-mTOR-Akt pathways, as well as menin expression were evaluated by immunoblotting. The impact of menin expression in the presence and absence of rapamycin was determinate upon Wound healing, migration and proliferation in MEFs and BON1 cells.

RESULTS: PDGF-BB markedly increased phosphorylation of mTORC2 substrate Akt, at serine 473 (S473) and threonine 450 (T450) in menin-/- MEFs but did not alter phosphorylation of mTORC1 substrates ribosomal protein S6 or eIF4B. Acute rapamycin treatment by mTORC1-S6 inhibition caused a greater enhancement of Akt phosphorylation on S473 in menin-/- cells as compared to menin+/+ MEFs (116% vs 38%). Chronic rapamycin treatment, which inhibits both mTORC1and 2, reduced Akt phosphorylation of S473 to a lesser extent in menin-/- MEFs than menin+/+ MEFs (25% vs 75%). Silencing of menin expression in human PNET cell line (BON1) also enhanced Akt phosphorylation at S473, but not activation of mTORC1. Interestingly, silencing menin in BON1 cells elevated S473 phosphorylation of Akt in both acute and chronic treatments with rapamycin. Finally, we show that the inhibitory effect of rapamycin on serum mediated wound healing and cell migration is impaired in menin-/- MEFs, as well as in menin-silenced BON1 cells.

CONCLUSIONS: Menin is involved in regulatory mechanism between the two mTOR complexes, and its reduced expression is accompanied with increased mTORC2-Akt signaling, which consequently impairs anti-migratory effect of rapamycin.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
Akt, MEN1, PI3K, PNET, Rapamycin, mTOR
National Category
Cell Biology
Identifiers
urn:nbn:se:uu:diva-363616 (URN)10.1186/s12964-018-0278-2 (DOI)000446362600001 ()30285764 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/895
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-12-03Bibliographically approved
Crona, J., Backman, S., Welin, S., Taieb, D., Hellman, P., Stålberg, P., . . . Pacak, K. (2018). RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective. Cancers, 10(12), Article ID 518.
Open this publication in new window or tab >>RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective
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2018 (English)In: Cancers, ISSN 2072-6694, Vol. 10, no 12, article id 518Article in journal (Refereed) Published
Abstract [en]

Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
pheochromocytoma, paraganglioma, adrenocortical carcinoma, adrenal tumor, pan-cancer analysis, neural crest, neuroendocrine
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-375237 (URN)10.3390/cancers10120518 (DOI)000455199200056 ()30558313 (PubMedID)
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-01-29Bibliographically approved
Backman, S., Norlén, O., Eriksson, B., Skogseid, B., Stålberg, P. & Crona, J. (2017). Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing. Anticancer Research, 37(2), 705-712
Open this publication in new window or tab >>Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing
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2017 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 2, p. 705-712Article in journal (Refereed) Published
Abstract [en]

Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.

PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.

RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.

CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

Keywords
MTOR, PNET, biomarker, next-generation sequencing
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-320669 (URN)10.21873/anticanres.11367 (DOI)000396901200038 ()28179320 (PubMedID)
Available from: 2017-04-23 Created: 2017-04-23 Last updated: 2018-06-04Bibliographically approved
Antonodimitrakis, P. C., Olofsson, H., Grimelius, L., Sundin, A., Wassberg, C., Granberg, D., . . . Eriksson, B. (2017). Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study. International Journal of Endocrine Oncology, 4(1), 9-22
Open this publication in new window or tab >>Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study
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2017 (English)In: International Journal of Endocrine Oncology, Vol. 4, no 1, p. 9-22Article in journal (Refereed) Published
Abstract [en]

Aim: Vasoactive intestinal polypeptide producing neuroendocrine tumors are rare and cause severe hormonal symptoms. Patients/methods: Eighteen patients with vasoactive intestinal polypeptide producing neuroendocrine tumors were analyzed with reviews of medical records, radiology and tumor tissue specimens. Results: Twelve patients (67%) had liver metastases at diagnosis. Chemotherapy, somatostatin analogs and interferon were given as medical therapies. Streptozocin/5-fluorouracil produced an objective response in 40% of the evaluable patients. Somatostatin analogs gave a clinical/biochemical response in eight out of nine patients. Transarterial embolization of the liver and peptide receptor radionuclide therapy was given to refractory cases. Sixteen patients died during the observation period. The median overall survival from diagnosis was 102 months. Conclusion: Systemic chemotherapy and somatostatin analogs should be given in cases of advanced disease or for hormonal symptoms.

Keywords
chemotherapy, IFN-α, neuroendocrine tumors, pancreas, somatostatin analogs, survival, vasoactive intestinal polypeptide
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-342674 (URN)10.2217/ije-2016-0012 (DOI)000426222300003 ()
Available from: 2018-02-22 Created: 2018-02-22 Last updated: 2018-03-23Bibliographically approved
Stålberg, K., Crona, J., Razmara, M., Taslica, D., Skogseid, B. & Ståhlberg, P. (2016). An Integrative Genomic Analysis of Formalin Fixed Paraffin-Embedded Archived Serous Ovarian Carcinoma Comparing Long-term and Short-term Survivors. International Journal of Gynecological Cancer, 26(6), 1027-1032
Open this publication in new window or tab >>An Integrative Genomic Analysis of Formalin Fixed Paraffin-Embedded Archived Serous Ovarian Carcinoma Comparing Long-term and Short-term Survivors
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2016 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, no 6, p. 1027-1032Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

This study aimed to perform an integrative genetic analysis of patients with matched serous ovarian cancer having long-term or short-term survival using formalin fixed paraffin-embedded (FFPE) tissue samples.

METHODS:

All patients with serous ovarian carcinoma who underwent surgery between 1998 and 2007 at the Department of Gynaecology, Uppsala University Hospital, Sweden were considered. From this cohort, we selected biomaterial from 2 groups of patients with long-term and short-term survival matched for age, stage, histologic grade, and outcome of surgery. Genomic DNA from FFPE sample was analyzed with SNP array and targeted next-generation sequencing of 26 genes.

RESULTS:

Forty-three samples (primary tumors and metastases) from 23 patients were selected for genomic profiling, the survival in the subgroups were 134 and 36 months, respectively. We observed a tendency toward increased genomic instability in those with long-term survival with higher proportion of somatic copy number alterations (P = 0.083) and higher average ploidy (P = 0.037). TP53 mutations were found in 50% of the patients. Frequency of TP53 mutations did not differ between the survival groups (P = 0.629).

CONCLUSIONS:

We validated both previous genomic findings in ovarian cancer and the proposed association between increased genomic instability and better survival. These results exemplify that analysis of genomic biomarkers is feasible on archived FFPE tissue.

Keywords
serous ovarian carcinoma
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-295178 (URN)10.1097/IGC.0000000000000721 (DOI)000383953500007 ()
Funder
Swedish Cancer Society
Available from: 2016-06-03 Created: 2016-06-03 Last updated: 2017-11-30Bibliographically approved
Crona, J. & Skogseid, B. (2016). Genetics of neuroendocrine tumors. European Journal of Endocrinology, 174(6), R275-R290
Open this publication in new window or tab >>Genetics of neuroendocrine tumors
2016 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 174, no 6, p. R275-R290Article, review/survey (Refereed) Published
Abstract [en]

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-299768 (URN)10.1530/EJE-15-0972 (DOI)000377114700005 ()27165966 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-07-27 Created: 2016-07-27 Last updated: 2017-11-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7046-9654

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