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5. The evolutionary history of metastatic pancreatic neuroendocrine tumours reveals a therapy driven route to high‐grade transformation.

Author

Backman, Samuel, Botling, Johan, Nord, Helena, Ghosal, Suman, Stålberg, Peter, Juhlin, C. Christofer, Almlöf, Jonas, Sundin, Anders, Zhang, Liang, Moens, Lotte, Eriksson, Barbro, Welin, Staffan, Hellman, Per, Skogseid, Britt, Pacak, Karel, Mollazadegan, Kazhan, Åkerström, Tobias, and Crona, Joakim

Subjects
NUCLEOTIDE sequencing, NEUROENDOCRINE tumors, CONVERGENT evolution, GENETIC variation, PUBLIC domain (Copyright law)
Abstract

Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high‐grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high‐grade disease. We performed multi‐omics analysis (genome/exome sequencing, total RNA‐sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post‐alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high‐grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high‐grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high‐grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Primary Aldosteronism

Author

Hellman, Per, Young, William F., Jr., Shifrin, Alexander L., editor, Raffaelli, Marco, editor, Randolph, Gregory W., editor, and Gimm, Oliver, editor

Published
2021
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8. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause

Author

Zhou, Junhua, Azizan, Elena A. B., Cabrera, Claudia P., Fernandes-Rosa, Fabio L., Boulkroun, Sheerazed, Argentesi, Giulia, Cottrell, Emily, Amar, Laurence, Wu, Xilin, O’Toole, Sam, Goodchild, Emily, Marker, Alison, Senanayake, Russell, Garg, Sumedha, Åkerström, Tobias, Backman, Samuel, Jordan, Suzanne, Polubothu, Satyamaanasa, Berney, Daniel M., Gluck, Anna, Lines, Kate E., Thakker, Rajesh V., Tuthill, Antoinette, Joyce, Caroline, Kaski, Juan Pablo, Karet Frankl, Fiona E., Metherell, Lou A., Teo, Ada E. D., Gurnell, Mark, Parvanta, Laila, Drake, William M., Wozniak, Eva, Klinzing, David, Kuan, Jyn Ling, Tiang, Zenia, Gomez Sanchez, Celso E., Hellman, Per, Foo, Roger S. Y., Mein, Charles A., Kinsler, Veronica A., Björklund, Peyman, Storr, Helen L., Zennaro, Maria-Christina, and Brown, Morris J.

Published
2021
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10. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Author

Cromer, M, Choi, Murim, Nelson-Williams, Carol, Fonseca, Annabelle, Kunstman, John, Korah, Reju, Overton, John, Mane, Shrikant, Kenney, Barton, Malchoff, Carl, Stalberg, Peter, Akerström, Göran, Westin, Gunnar, Hellman, Per, Carling, Tobias, Björklund, Peyman, and Lifton, Richard

Subjects
YY1, adenylyl cyclase, cAMP, exome sequencing, insulinoma, Adenylyl Cyclases, Adolescent, Adult, Aged, Aged, 80 and over, Base Sequence, Binding Sites, Blood Glucose, Calcium, Calcium Channels, Cohort Studies, Cyclic AMP, Female, Gene Expression Regulation, Humans, Insulin, Insulin-Secreting Cells, Insulinoma, Male, Middle Aged, Molecular Sequence Data, Mutation, Missense, Pancreatic Neoplasms, Protein Binding, YY1 Transcription Factor
Abstract

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

Published
2015

14. The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation

Author

Backman, Samuel, primary, Botling, Johan, additional, Nord, Helena, additional, Ghosal, Suman, additional, Stalberg, Peter, additional, Juhlin, C Christofer, additional, Almlof, Jonas, additional, Sundin, Anders, additional, Zhang, Liang, additional, Moens, Lotte, additional, Eriksson, Barbro, additional, Welin, Staffan, additional, Hellman, Per, additional, Skogseid, Britt, additional, Pacak, Karel, additional, Mollazadegan, Kazhan, additional, Akerstrom, Tobias, additional, and Crona, Joakim, additional

Published
2024
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21. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort

Author

Williams, Tracy Ann, Gomez-Sanchez, Celso E, Funder, John W, Reincke, Martin, Adolf, Christian, Amar, Laurence, Auchus, Richard J, Bartsch, Detlef K, Baudrand, Rene, Beuschlein, Felix, Björklund, Peyman, Brown, Morris J, Burrello, Jacopo, Carey, Robert M, Catena, Cristiana, Connell, John M, Deinum, Jaap, Dekkers, Tanja, Fahey, Thomas J, 3rd, Fallo, Francesco, Fardella, Carlos E., Giacchetti, Gilberta, Giraudo, Giuseppe, Hellman, Per, Januszewicz, Andrzej, Kitamoto, Kanako Kiriyama, Kline, Gregory A, Kocjan, Tomaz, Lenders, Jacques W M, Mantero, Franco, Miller, Barbra S, Morimoto, Ryo, Mulatero, Paolo, Naruse, Mitsuhide, Nishikawa, Tetsuo, Pham, Uyen, Plouin, Pierre-François, Prejbisz, Alexander, Quinkler, Marcus, Rottenkolber, Marietta, Rump, Christian L, Satoh, Fumitoshi, Sechi, Leonardo A, Stowasser, Michael, Umakoshi, Hironobu, Veglio, Franco, Widimský, Jirí, Jr, Willenberg, Holger S, Young, William F, Jr, Williams, Tracy A, Kitamoto, Kanako K, and Prejbisz, Aleksander

Published
2017
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23. Radiation dosimetry of para-chloro-2-[18F]fluoroethyl-etomidate: a PET tracer for adrenocortical imaging.

Author

Silins, Isabella, Moreno, Adrian, Wall, Anders, Aigbirhio, Franklin, Gurnell, Mark, Brown, Morris, Roslin, Sara, Antoni, Gunnar, Hellman, Per, Sundin, Anders, and Lubberink, Mark

Subjects
RADIATION dosimetry, ADRENAL glands, POSITRON emission tomography, ABSORBED dose, METHYL formate, THERMOLUMINESCENCE dosimetry
Abstract

Background: [11C]metomidate, a methyl ester analogue of etomidate, is used for positron emission tomography of adrenocortical cancer, and has been tested in recent clinical trials for lateralization in primary aldosteronism (PA). However, in PA, visualization as well as uptake quantification are hampered by the tracer's rather high non-specific liver uptake, and its overall clinical usefulness is also limited by the short 20-minute half-life of carbon-11. Therefore, we evaluated para-chloro-2-[18F]fluoroethyl-etomidate, [18F]CETO, a fluorine-18 (T1/2=109.8 min) analogue, as a potential new adrenocortical PET tracer. The aim of this study was to assess radiation dosimetry of [18F]CETO. Results: [18F]CETO showed a high uptake in adrenal glands, still increasing at 5 h post injection. Adrenal glands (absorbed dose coefficients 0.100 ± 0.032 mGy/MBq in males and 0.124 ± 0.013 mGy/MBq in females) received the highest absorbed dose. The effective dose coefficient was 20 µSv/MBq. Conclusions: [18F]CETO has a favourable biodistribution in humans for adrenal imaging. The effective dose for a typical clinical PET examination with 200 MBq [18F]CETO is 4 mSv. Trial registration: ClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, URL: https://clinicaltrials.gov/ct2/show/NCT05361083. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Improved health‐related quality of life during peptide receptor radionuclide therapy in patients with neuroendocrine tumours

Author

Edfeldt, Katarina, Hellman, Per, Granberg, Dan, Lagergren, Pernilla, Thiis‐Evensen, Espen, Sundin, Anders, Andersson, Camilla, Edfeldt, Katarina, Hellman, Per, Granberg, Dan, Lagergren, Pernilla, Thiis‐Evensen, Espen, Sundin, Anders, and Andersson, Camilla

Abstract

Neuroendocrine tumours (NETs) can arise in different locations in the body, and may give rise to hormonal symptoms, which amongst other factors may affect patients' health-related quality of life (HRQoL). Up to four cycles of peptide receptor radionuclide therapy (PRRT) have been shown effective for symptom alleviation and prolonging progression-free survival. The aim of this study was to assess the patient's perspective regarding changes in their HRQoL during PRRT. HRQoL was assessed using the questionnaires for cancer in general, EORTC QLQ-C30, and the gastrointestinal NET-specifically EORTC QLQ-GINET21. Patients with NET (n = 204) rated their HRQoL before PRRT cycles one and four. The medical records of patients were reviewed and their HRQoL was compared to a matched reference population (n = 4910). HRQoL was found to improve during PRRT in aspects of global quality of life; role, social, and emotional functioning, and multiple symptom relief. Potential risk groups for worse HRQoL during PRRT were patients with overweight (BMI >25) who completed four cycles of PRRT and older patients (>65 years old). In conclusion, we found that PRRT improves HRQoL in patients with NETs. The results of this study may be used to improve person-centred care.

Published
2023
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43. Carcinoid Neoplasms

Author

Åkerström, Göran, Hellman, Per, Bland, Kirby I., editor, Büchler, Markus W., editor, Csendes, Attila, editor, Sarr, Michael G., editor, Garden, O. James, editor, and Wong, John, editor

Published
2009
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