| 1. |
- Karakaya, Sinan, et al.
(författare)
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Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2 & alpha; correlate to an aggressive tumor phenotype. We show that HIF-2 & alpha; localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2 & alpha; was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2 & alpha; expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.
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| 2. |
- Muth, Andreas, 1974, et al.
(författare)
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Prevalence of Germline Mutations in Patients with Pheochromocytoma or Abdominal Paraganglioma and Sporadic Presentation: A Population-Based Study in Western Sweden.
- 2012
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Ingår i: World journal of surgery. - : Springer Science and Business Media LLC. - 1432-2323 .- 0364-2313. ; 36:6, s. 1389-94
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Germline mutations in the susceptibility genes RET, SDHB, SDHD, and VHL have been reported in 7.5-24% of patients with pheochromocytoma (Pheo) or paraganglioma (PGL) and sporadic presentation. The purpose of the present study was to establish population-based data on the frequency of germline mutations in patients with apparently sporadic Pheo or abdominal PGL in Western Sweden. METHODS: From the Swedish National Cancer Registry, all patients with Pheo or PGL in Western Sweden (population 1.72 million) registered between 1958 and 2009 were identified (n=256). Patients were characterized using register data, hospital records, and clinical interviews. All living patients with Pheo or abdominal PGL and sporadic presentation (n=81) were invited to genetic screening; 71 patients accepted. Germline mutations were investigated by using direct sequencing for point mutations in RET, SDHB, SDHD, and VHL, and multiplex ligation-dependent probe amplification for gross deletions in SDHB, SDHC, SDHD, and VHL. Plasma or urinary metanephrines and/or urinary catecholamines were used for biochemical follow-up. RESULTS: The prevalence of germline mutations was 5.6%. Mutations were only seen in RET (n=1) and SDHB (n=3). Notably, in the patients with SDHB mutations, no malignant phenotype was observed during a mean follow-up of 23.3years. CONCLUSIONS: The frequency of germline mutations in patients with apparently sporadic Pheo and abdominal PGL in Western Sweden was lower than in previous studies. Variations in reported frequencies of germline mutations in patients with clinically sporadic Pheo/PGL may reflect geographical differences or patient selection.
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| 3. |
- Tomic, Tajana Tesan, et al.
(författare)
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MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
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| 4. |
- Wilzén, Annica, et al.
(författare)
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Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes.
- 2016
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 138:9, s. 2201-11
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Tidskriftsartikel (refereegranskat)abstract
- One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p
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| 5. |
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| 6. |
- Abel, Andreas, 1974, et al.
(författare)
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A formalized proof of strong normalization for guarded recursive types
- 2014
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Ingår i: Lecture Notes in Computer Science: 12th Asian Symposium on Programming Languages and Systems, APLAS 2014 Singapore, 17-19 November 2014. - Cham : Springer International Publishing. - 0302-9743 .- 1611-3349. - 9783319127354 ; 8858, s. 140-158
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Konferensbidrag (refereegranskat)abstract
- We consider a simplified version of Nakano’s guarded fixed-point types in a representation by infinite type expressions, defined coinductively. Smallstep reduction is parametrized by a natural number “depth” that expresses under how many guards we may step during evaluation. We prove that reduction is strongly normalizing for any depth. The proof involves a typed inductive notion of strong normalization and a Kripke model of types in two dimensions: depth and typing context. Our results have been formalized in Agda and serve as a case study of reasoning about a language with coinductive type expressions.
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| 7. |
- Abel, Andreas, 1974, et al.
(författare)
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A Graded Modal Dependent Type Theory with a Universe and Erasure, Formalized
- 2023
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Ingår i: Proceedings of the ACM on Programming Languages. - 2475-1421. ; 7:ICFP, s. 920-954
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Tidskriftsartikel (refereegranskat)abstract
- We present a graded modal type theory, a dependent type theory with grades that can be used to enforce various properties of the code. The theory has Pi-types, weak and strong Sigma-types, natural numbers, an empty type, and a universe, and we also extend the theory with a unit type and graded Sigma-types. The theory is parameterized by a modality, a kind of partially ordered semiring, whose elements (grades) are used to track the usage of variables in terms and types. Different modalities are possible. We focus mainly on quantitative properties, in particular erasure: with the erasure modality one can mark function arguments as erasable. The theory is fully formalized in Agda. The formalization, which uses a syntactic Kripke logical relation at its core and is based on earlier work, establishes major meta-theoretic properties such as subject reduction, consistency, normalization, and decidability of definitional equality. We also prove a substitution theorem for grade assignment, and preservation of grades under reduction. Furthermore we study an extraction function that translates terms to an untyped λ-calculus and removes erasable content, in particular function arguments with the "erasable"grade. For a certain class of modalities we prove that extraction is sound, in the sense that programs of natural number type have the same value before and after extraction. Soundness of extraction holds also for open programs, as long as all variables in the context are erasable, the context is consistent, and erased matches are not allowed for weak Sigma-types.
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| 8. |
- Abel, Andreas, 1974, et al.
(författare)
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A Unified View of Modalities in Type Systems
- 2020
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Ingår i: Proceedings of the ACM on Programming Languages. - : Association for Computing Machinery (ACM). - 2475-1421. ; 4:ICFP
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Tidskriftsartikel (refereegranskat)abstract
- We propose to unify the treatment of a broad range of modalities in typed lambda calculi. We do so by defining a generic structure of modalities, and show that this structure arises naturally from the structure of intuitionistic logic, and as such finds instances in a wide range of type systems previously described in literature. Despite this generality, this structure has a rich metatheory, which we expose.
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| 9. |
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| 10. |
- Abel, Andreas, 1974
(författare)
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Compositional coinduction with sized types
- 2016
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Ingår i: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - Cham : Springer International Publishing. - 0302-9743 .- 1611-3349.
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Konferensbidrag (refereegranskat)
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