71 results on '"Martin Bäckdahl"'
Search Results
2. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.
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Tobias Åkerström, Joakim Crona, Alberto Delgado Verdugo, Lee F Starker, Kenko Cupisti, Holger S Willenberg, Wolfram T Knoefel, Wolfgang Saeger, Alfred Feller, Julian Ip, Patsy Soon, Martin Anlauf, Pier F Alesina, Kurt W Schmid, Myriam Decaussin, Pierre Levillain, Bo Wängberg, Jean-Louis Peix, Bruce Robinson, Jan Zedenius, Martin Bäckdahl, Stefano Caramuta, K Alexander Iwen, Johan Botling, Peter Stålberg, Jean-Louis Kraimps, Henning Dralle, Per Hellman, Stan Sidhu, Gunnar Westin, Hendrik Lehnert, Martin K Walz, Göran Åkerström, Tobias Carling, Murim Choi, Richard P Lifton, and Peyman Björklund
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Medicine ,Science - Abstract
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.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.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
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- 2012
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3. Supplementary Tables S1-S2 from Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior
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Catharina Larsson, Tomas J. Ekström, Martin Bäckdahl, Jia-Jing Lee, Mohsen Karimi, Nimrod Kiss, and Janos Geli
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Supplementary Tables S1-S2 from Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior
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- 2023
4. Data from Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior
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Catharina Larsson, Tomas J. Ekström, Martin Bäckdahl, Jia-Jing Lee, Mohsen Karimi, Nimrod Kiss, and Janos Geli
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Purpose: This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes.Experimental Design: A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16INK4A, CDH1, DCR2, RARB, RASSF1A, NORE1A, TP73, APC, DAPK1, p14ARF, and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis.Results: Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02).Conclusion: We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.
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- 2023
5. HRAS mutation prevalence and associated expression patterns in pheochromocytoma
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Adam Stenman, C. Christofer Juhlin, Peter Söderkvist, Oliver Gimm, Martin Bäckdahl, Ida Gustavsson, Catharina Larsson, Laurent Brunaud, Jenny Welander, Department of Oncology-Pathology [Karolinska Institutet], Karolinska Institutet [Stockholm], Cancer Center Karolinska [Karolinska Institutet] (CCK), Division of Clinical Chemistry, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University (LIU), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Chirurgie Digestive Hépatobiliaire et Endocrine [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Department of Molecular Medicine and Surgery and Center for Molecular Medicine, and Departmentof Surgery [Karolinska Institutet]
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0301 basic medicine ,Male ,Cancer Research ,[SDV]Life Sciences [q-bio] ,Adrenal Gland Neoplasms ,Gene mutation ,Sporadic Pheochromocytomas ,Exon ,0302 clinical medicine ,Ras Mutations ,Mutation frequency ,Hypoxia ,Research Articles ,Genetics ,Regulation of gene expression ,Aged, 80 and over ,Middle Aged ,Defines ,3. Good health ,Gene Expression Regulation, Neoplastic ,Hereditary ,030220 oncology & carcinogenesis ,Female ,Research Article ,Adult ,Somatic Mutations ,Adolescent ,Pheochromocytoma ,Biology ,Carcinomas ,Paraganglioma ,03 medical and health sciences ,Gene-Mutations ,Young Adult ,medicine ,Humans ,HRAS ,Gene ,Aged ,Klinisk medicin ,medicine.disease ,H-Ras ,Gene expression profiling ,030104 developmental biology ,Genes, ras ,Mutation ,Cancer research ,Clinical Medicine - Abstract
Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase-signaling pathways. Funding Agencies|Swedish Cancer Foundation; StratCan; Swedish Research Council; Cancer Research Foundations of Radiumhemmet; Karolinska Institutet; Stockholm County Council
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- 2016
6. TERT promoter hypermethylation is associated with poor prognosis in adrenocortical carcinoma
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Na Wang, Martin Bäckdahl, Tobias Carling, Timothy D. Murtha, Omid Fotouhi, Johan O. Paulsson, Ninni Mu, C. Christofer Juhlin, Reju Korah, Adam Stenman, Fredrika Svahn, and Catharina Larsson
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Adult ,Male ,0301 basic medicine ,Telomerase ,Gene Dosage ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Adrenocortical Carcinoma ,Genetics ,Humans ,Telomerase reverse transcriptase ,RNA, Messenger ,Promoter Regions, Genetic ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Regulation of gene expression ,General Medicine ,Methylation ,DNA Methylation ,Middle Aged ,Telomere ,Prognosis ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,030104 developmental biology ,Real-time polymerase chain reaction ,CpG site ,Genetic Loci ,030220 oncology & carcinogenesis ,Mutation ,DNA methylation ,Female - Abstract
Telomere maintenance, most commonly achieved by telomerase activation through induction of the telomerase reverse transcriptase (TERT) gene, is required for cell immortalization, a hallmark of cancer. Adrenocortical carcinoma (ACC) is an endocrine tumor for which TERT promoter mutations and telomerase activation have been reported. The present study assessed alterations of the TERT gene locus and telomere length in relation to clinical characteristics in ACC. In total, 38 cases of ACC with known TERT promoter mutational status were included. TERT promoter methylation densities were assessed by pyrosequencing, and TERT copy numbers and telomere length were determined by quantitative polymerase chain reaction analysis, followed by comparison of the mRNA expression of TERT and clinical parameters. The ACC tissue samples showed increased TERT copy numbers, compared with normal adrenal tissue (NAT) samples (P=0.001). Mutually exclusive TERT copy number gains or promoter mutation were present in 70% of the ACC samples. The ACC tissues exhibited higher levels of CpG promoter methylation of all eight CpG sites investigated within the ‑578 to ‑541 bp (Region A), compared with the NATs (P=0.001). High methylation density at this region was associated with metastatic disease and/or relapse, poor survival rates and higher European Network for the Study of Adrenal Tumor stage (P
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- 2018
7. Telomerase-Dependent and Independent Telomere Maintenance and its Clinical Implications in Medullary Thyroid Carcinoma
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Na Wang, Jan Zedenius, Anastasios Sofiadis, Vladana Vukojević, Dawei Xu, Martin Bäckdahl, Catharina Larsson, and Anders Höög
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Adult ,Male ,medicine.medical_specialty ,Telomerase ,Adolescent ,Endocrinology, Diabetes and Metabolism ,DNA Mutational Analysis ,Clinical Biochemistry ,Context (language use) ,Biology ,Biochemistry ,Thyroid carcinoma ,Young Adult ,Endocrinology ,Telomere Homeostasis ,Internal medicine ,medicine ,Humans ,Telomerase reverse transcriptase ,Thyroid Neoplasms ,Aged ,Southern blot ,Aged, 80 and over ,JCEM Online: Advances in Genetics ,Proto-Oncogene Proteins c-ret ,Biochemistry (medical) ,Middle Aged ,Telomere ,Prognosis ,Survival Analysis ,Molecular biology ,Carcinoma, Neuroendocrine ,HEK293 Cells ,Telomere maintenance via telomerase ,Female ,HeLa Cells - Abstract
Context: Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma. Setting and Design: In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence. Results: TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the α− and β−-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024). Conclusions: Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma.
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- 2014
8. The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors
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C. Christofer Juhlin, Tiantian Liu, Martin Bäckdahl, Adam Andreasson, Tobias Carling, Reju Korah, Na Wang, Taylor C. Brown, James M. Healy, Manju L. Prasad, Dawei Xu, and Catharina Larsson
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Adult ,Male ,Cancer Research ,Telomerase ,endocrine ,Adolescent ,TERT ,Endocrinology, Diabetes and Metabolism ,Adrenal Gland Neoplasm ,Adrenal Gland Neoplasms ,Pheochromocytoma ,Biology ,telomerase ,Real-Time Polymerase Chain Reaction ,medicine.disease_cause ,Adrenocortical adenoma ,Paraganglioma ,Young Adult ,Endocrinology ,Adrenocortical Carcinoma ,medicine ,Humans ,Adrenocortical carcinoma ,RNA, Messenger ,Promoter Regions, Genetic ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Mutation ,Reverse Transcriptase Polymerase Chain Reaction ,Research ,Middle Aged ,Prognosis ,medicine.disease ,Reverse transcriptase ,Telomere ,Survival Rate ,Oncology ,adrenocortical tumor ,Case-Control Studies ,Adrenocortical Adenoma ,Cancer research ,Female ,Neoplasm Recurrence, Local ,Follow-Up Studies - Abstract
The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization. Recent studies have demonstrated a transcriptional activation role for theTERTpromoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications. Although telomerase activation is known in adrenal tumors, the underlying mechanisms are not established. We assessed C228T and C250TTERTmutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation. A total of 199 tumors were evaluated, including 34 adrenocortical carcinomas (ACC), 47 adrenocortical adenomas (ACA), 105 pheochromocytomas (PCC; ten malignant and 95 benign), and 13 abdominal paragangliomas (PGL; nine malignant and four benign).TERTexpression levels were determined by quantitative RT-PCR. The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028). C228T was also observed in one benign PCC and in one metastatic PGL. The C250T mutation was not observed in any case. In the ACC and PGL groups,TERTmutation-positive cases exhibitedTERTexpression, indicating telomerase activation; however, since expression was also revealed inTERTWT cases, this could denote additional mechanisms ofTERTactivation. To conclude, theTERTpromoter mutation C228T is a recurrent event associated withTERTexpression in ACCs, but rarely occurs in PGL and PCC. The involvement of theTERTgene in ACC represents a novel mutated gene in this entity.
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- 2014
9. Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma
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Adam Andreasson, Michael Brauckhoff, Martin Bäckdahl, Catharina Larsson, Peter Söderkvist, Oliver Gimm, and Jenny Welander
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Adult ,Male ,Cancer Research ,DNA Copy Number Variations ,Endocrinology, Diabetes and Metabolism ,Molecular Sequence Data ,Adrenal Gland Neoplasms ,Pheochromocytoma ,Biology ,Cohort Studies ,Paraganglioma ,Endocrinology ,Germline mutation ,Basic Helix-Loop-Helix Transcription Factors ,Biomarkers, Tumor ,medicine ,Humans ,Amino Acid Sequence ,Copy-number variation ,Gene ,Exome ,Neoplasm Staging ,Oligonucleotide Array Sequence Analysis ,Genetic testing ,Genetics ,Sequence Homology, Amino Acid ,medicine.diagnostic_test ,Microarray analysis techniques ,Gene Expression Profiling ,Exons ,Middle Aged ,Prognosis ,medicine.disease ,Oncology ,Mutation ,Female ,Follow-Up Studies - Abstract
Pheochromocytomas and paragangliomas are neuroendocrine tumors that arise from neural crest-derived cells of the adrenal medulla and the extra-adrenal paraganglia. They cause hypertension due to an abnormally high production of catecholamines (mainly adrenaline and noradrenaline), with symptoms including recurrent episodes of headache, palpitations and sweating, and an increased risk of cardiovascular disease. Malignancy in the form of distant metastases occurs in 10-15% of the patients. The malignant cases are difficult to predict and cure, and have a poor prognosis. About a third of pheochromocytomas and paragangliomas are caused by hereditary mutations in a growing list of known susceptibility genes. However, the cause of the remaining, sporadic, tumors is still largely unknown. The aim of this thesis project has been to further characterize the genetic background of pheochromocytomas and paragangliomas, with a focus on the sporadic tumors.First, we investigated the role of the genes known from the familial tumors in the sporadic form of the disease. By studying mutations, copy number variations, DNA methylation and gene expression, we found that many of the known susceptibility genes harbor somatic alterations in sporadic pheochromocytomas. Particularly, we found that the NF1 gene, which plays an important role in suppressing cell growth and proliferation by regulating the RASMAPK pathway, was inactivated by mutations in more than 20% of the cases. The mutations occurred together with deletions of the normal allele and were associated with a reduced NF1 gene expression and a specific hormone profile. We also detected activating mutations in the gene EPAS1, which encodes HIF-2α, in a subset of sporadic cases. Microarray analysis of gene expression showed that several genes involved in angiogenesis and cell metabolism were upregulated in EPAS1-mutated tumors, which is in agreement with the role of HIF-2α in the cellular response to hypoxia. In order to comprehensively investigate all the known susceptibility genes in a larger patient cohort, we designed a targeted next-generation sequencing approach and could conclude that it was fast and cost-efficient for genetic testing of pheochromocytomas and paragangliomas. The results showed that about 40% of the sporadic cases had mutations in the tested genes. The majority of the mutations were somatic, but some apparently sporadic cases in fact carried germline mutations. Such knowledge of the genetic background can be of importance to facilitate early detection and correct treatment of pheochromocytomas, paragangliomas and potential co-occurring cancers, and also to identify relatives that might be at risk. By sequencing all the coding regions of the genome, the exome, we then identified recurrent activating mutations in a novel gene, in which mutations have previously only been reported in subgroups of brain tumors. The identified mutations are proposed to cause constitutive activation of the encoded receptor tyrosine kinase, resulting in the activation of downstream kinase signaling pathways that promote cell growth and proliferation.In summary, the studies increase our biological understanding of pheochromocytoma and paraganglioma, and possibly also co-occurring cancers in which the same genes and pathways are involved. Together with the findings of other scientific studies, our results may contribute to the development of future treatment options.
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- 2014
10. TheVHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas
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Fredrika Svahn, Martin Bäckdahl, Nimrod B Kiss, Luqman Sulaiman, C. Christofer Juhlin, Stefano Caramuta, Anders Höög, Adam Andreasson, and Catharina Larsson
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DNA promoter methylation ,Cancer Research ,SDHB ,Molecular Sequence Data ,Adrenal Gland Neoplasms ,Down-Regulation ,Pheochromocytoma ,Biology ,Epigenesis, Genetic ,Paraganglioma ,VHL ,medicine ,Humans ,MEN1 ,RNA, Messenger ,Epigenetics ,Promoter Regions, Genetic ,Molecular Biology ,Base Sequence ,qRT-PCR ,Methylation ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,pyrosequencing ,Von Hippel-Lindau Tumor Suppressor Protein ,Abdominal Neoplasms ,Case-Control Studies ,DNA methylation ,gene expression ,Cancer research ,SDHD ,Research Paper - Abstract
Pheochromocytoma (PCC) and abdominal paraganglioma (PGL) are neuroendocrine tumors that present with clinical symptoms related to increased catecholamine levels. About a third of the cases are associated with constitutional mutations in pre-disposing genes, of which some may also be somatically mutated in sporadic cases. However, little is known about inactivating epigenetic events through promoter methylation in these very genes. Using bisulphite pyrosequencing we assessed the methylation density of 11 PCC/PGL disease genes in 96 tumors (83 PCCs and 13 PGLs) and 34 normal adrenal references. Gene expression levels were determined by quantitative RT-PCR. Both tumors and normal adrenal samples exhibited low methylation index (MetI) in the EGLN1 (PDH2), MAX, MEN1, NF1, SDHB, SDHC, SDHD, SDHAF2 (SDH5), and TMEM127 promoters, not exceeding 10% in any of the samples investigated. Aberrant RET promoter methylation was observed in two cases only. For the VHL gene we found increased MetI in tumors as compared with normal adrenals (57% vs. 27%; P < 0.001), in malignant vs. benign tumors (63% vs. 55%; P < 0.05), and in PGL vs. PCC (66% vs. 55%; P < 0.0005). Decreased expression of the VHL gene was observed in all tumors compared with normal adrenals (P < 0.001). VHL MetI and gene expressions were inversely correlated (R = −0.359, P < 0.0001). Our results show that the VHL gene promoter has increased methylation compared with normal adrenals (MetI > 50%) in approximately 75% of PCCs and PGLs investigated, highlighting the role of VHL in the development of these tumors.
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- 2013
11. Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma
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Hong Xie, Martin Bäckdahl, Linkiat Lee, Deniz M. Ozata, Weng-Onn Lui, Jan Zedenius, Catharina Larsson, Pinar Akcakaya, Anders Höög, and Stefano Caramuta
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Adult ,Male ,Ribonuclease III ,Cancer Research ,over-expression ,Adolescent ,DGCR8 ,Endocrinology, Diabetes and Metabolism ,diagnostic ,Apoptosis ,Gene mutation ,Adrenocortical adenoma ,DEAD-box RNA Helicases ,Young Adult ,Endocrinology ,Cell Line, Tumor ,adrenocortical cancer ,microRNA ,Adrenocortical Carcinoma ,medicine ,Humans ,Adrenocortical carcinoma ,RNA, Messenger ,Drosha ,Aged ,Aged, 80 and over ,TARBP2 ,function ,biology ,Research ,RNA-Binding Proteins ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,MicroRNAs ,Oncology ,Adrenocortical Adenoma ,biology.protein ,Cancer research ,Immunohistochemistry ,Female ,Dicer - Abstract
Deregulation of microRNA (miRNA) expression in adrenocortical carcinomas (ACCs) has been documented to have diagnostic, prognostic, as well as functional implications. Here, we evaluated the mRNA expression ofDROSHA,DGCR8,DICER(DICER1),TARBP2, andPRKRA, the core components in the miRNA biogenesis pathway, in a cohort of 73 adrenocortical tumors (including 43 adenomas and 30 carcinomas) and nine normal adrenal cortices using a RT-qPCR approach. Our results show a significant over-expression ofTARBP2,DICER, andDROSHAin the carcinomas compared with adenomas or adrenal cortices (PTARBP2, but notDICERorDROSHA, is a strong molecular predictor to discriminate between adenomas and carcinomas. Functionally, we showed that inhibition of TARBP2 expression in human NCI-H295R ACC cells resulted in a decreased cell proliferation and induction of apoptosis. TARBP2 over-expression was not related to gene mutations; however, copy number gain of theTARBP2gene was observed in 57% of the carcinomas analyzed. In addition, we identified thatmiR-195andmiR-497could directly regulate TARBP2 and DICER expression in ACC cells. This is the first study to demonstrate the deregulation of miRNA-processing factors in adrenocortical tumors and to show the clinical and biological impact of TARBP2 over-expression in this tumor type.
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- 2013
12. Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas
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Jenny Welander, Oliver Gimm, Michael Brauckhoff, Catharina Larsson, Peter Söderkvist, Martin Bäckdahl, Tobias Sivlér, and Niyaz Hareni
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Heterozygote ,DNA Copy Number Variations ,endocrine system diseases ,SDHB ,DNA Mutational Analysis ,SDHA ,Pheochromocytoma ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Germline mutation ,Paraganglioma ,Genes, Neurofibromatosis 1 ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Promoter Regions, Genetic ,neoplasms ,Molecular Biology ,Alleles ,Germ-Line Mutation ,Genetics (clinical) ,Mutation ,Genetic disorder ,General Medicine ,Microarray Analysis ,medicine.disease ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Cancer research ,SDHD ,Gene Deletion ,Genome-Wide Association Study - Abstract
Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.
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- 2012
13. Anaplastic carcinoma of the thyroid gland: Treatment and outcome over 13 years at one institution
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Theodoros Foukakis, Inga-Lena Nilsson, Catharina Larsson, Jan Zedenius, Göran Wallin, Anders Höög, Martin Bäckdahl, and Ivan Segerhammar
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Thyroid ,Retrospective cohort study ,General Medicine ,medicine.disease ,Malignancy ,Surgery ,Thyroid carcinoma ,Radiation therapy ,Regimen ,medicine.anatomical_structure ,Oncology ,medicine ,Anaplastic carcinoma ,business ,Survival analysis - Abstract
Background Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy of the thyroid gland. Patients at our institution are treated with external radiotherapy up to 46 Gray (Gy) and low-dose doxorubicin prior to surgery. We retrospectively evaluated the outcome of ATC patients over a 13-year period. Methods Clinical, histopathological, and follow-up data for 59 patients diagnosed between 1997 and 2010 were collected and analyzed. Results Median age at diagnosis was 77 years. Female-male ratio was 2.5:1. Median survival from time of diagnosis was 3.3 months. Thirty-six patients completed the treatment protocol (including surgery), of whom one succumbed due to local tumor growth. In multivariate analysis, the only factor significantly associated with longer survival among operated patients was absence of metastases at diagnosis (P = 0.031). No impact on survival time was found for gender, extent of surgical resection, and absence of extrathyroidal invasion. Conclusions Despite aggressive treatment, survival rates in ATC patients remain low. Locoregional control is feasible for most patients, underscoring the importance of an intense, multimodal treatment regimen. Further oncological intervention is of crucial importance to achieve a better prognosis for ATC patients. J. Surg. Oncol. 2012; 106: 981–986. © 2012 Wiley Periodicals, Inc.
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- 2012
14. Transcriptional profiling enables molecular classification of adrenocortical tumours
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Janos Geli, Martin Bäckdahl, Bertil Hamberger, Cecilia Laurell, David Velázquez-Fernández, C. Christofer Juhlin, Anders Höög, Catharina Larsson, Magnus Kjellman, Kristina Lindsten, Joakim Lundeberg, Peter Nilsson, and Ulla Enberg
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Adenoma ,Adult ,Male ,medicine.medical_specialty ,Transcription, Genetic ,Endocrinology, Diabetes and Metabolism ,Biology ,Malignancy ,Endocrinology ,Molecular classification ,Neoplasms ,Internal medicine ,medicine ,Humans ,Survival analysis ,Aged ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,Adrenal Cortex Neoplasms ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Female ,Ubiquitin-Specific Proteases ,Ubiquitin Thiolesterase - Abstract
ObjectiveTumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5–2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.MethodsMicroarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.ResultsUnsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.ConclusionsAdrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.
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- 2009
15. Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas
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C Avci, Jamileh Hashemi, Catharina Larsson, Martin Bäckdahl, F Lundberg, Nimrod B Kiss, Janos Geli, Anders Höög, Tomas J. Ekström, David Velázquez-Fernández, and G Weber
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Cancer Research ,Pathology ,medicine.medical_specialty ,Sympathetic Nervous System ,SDHB ,Endocrinology, Diabetes and Metabolism ,Mutation, Missense ,Breast Neoplasms ,Pheochromocytoma ,Gene mutation ,Biology ,Malignancy ,Polymorphism, Single Nucleotide ,Metastasis ,Suppression, Genetic ,Endocrinology ,Peripheral Nervous System Neoplasms ,CDKN2A ,Cell Line, Tumor ,Tumor Suppressor Protein p14ARF ,medicine ,Humans ,Missense mutation ,Promoter Regions, Genetic ,Paraganglioma, Extra-Adrenal ,Osteosarcoma ,Reverse Transcriptase Polymerase Chain Reaction ,Genes, p16 ,Genetic Variation ,DNA Methylation ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Succinate Dehydrogenase ,Oncology ,DNA methylation ,Cancer research - Abstract
Pheochromocytomas and abdominal extra-adrenal paragangliomas are related to endocrine tumors of the sympathetic nervous system. Studies in animal models have shown that inactivation of the products of the cyclin dependent kinase inhibitor 2A (CDKN2A) gene locus, p16 INK4A and p14 ARF , promotes the development of pheochromocytoma, especially in malignant form. The present study evaluated the involvement of CDKN2A in human pheochromocytomas and abdominal extra-adrenal paragangliomas from 55 patients. Promoter methylation was assessed using quantitative Pyrosequencing and methylation-specific PCR, and mRNA expression was measured by quantitative real-time PCR. For p16, western blot analysis and sequencing were also performed. succinate dehydrogenase complex subunit B (SDHB) sequencing analysis included extra-adrenal paragangliomas, all tumors classified as malignant, and cases diagnosed at 30 years or younger. The p16 INK4A promoter was heavily methylated in a subset of paragangliomas, and this was significantly associated with malignancy (P
- Published
- 2008
16. The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma
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Filip Farnebo, Anders Höög, Natalia Natalishvili, Janos Geli, Catharina Larsson, Olle Larsson, Tomas J. Ekström, Theodoros Foukakis, Fredrik Lanner, Geoffrey J. Clark, Martin Bäckdahl, Nimrod B Kiss, and Per Kogner
- Subjects
endocrine system ,Cancer Research ,Endocrinology, Diabetes and Metabolism ,Apoptosis ,Pheochromocytoma ,Biology ,Transfection ,medicine.disease_cause ,PC12 Cells ,Paraganglioma ,Endocrinology ,medicine ,Animals ,Humans ,Sulfites ,Gene silencing ,RNA, Messenger ,Promoter Regions, Genetic ,Adaptor Proteins, Signal Transducing ,Aged ,Monomeric GTP-Binding Proteins ,Tumor Suppressor Proteins ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Phenotype ,Molecular biology ,Rats ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Abdominal Neoplasms ,Apoptosis Regulatory Proteins ,Adrenal medulla ,Carcinogenesis - Abstract
NORE1A (RASSF5) and RASSF1A are newly described Ras effectors with tumour suppressor functions. Both molecules are frequently inactivated in various cancers. In this study, we aimed to explore the potential involvement of NORE1A and RASSF1A in pheochromocytoma and abdominal paraganglioma tumorigenesis. A panel of 54 primary tumours was analysed for NORE1A and RASSF1A mRNA expression by TaqMan quantitative RT-PCR. Furthermore, NORE1A and RASSF1A promoter methylation was assessed by combined bisulphite restriction endonuclease assay and methylation-sensitive Pyrosequencing respectively. The anti-tumorigenic role of NORE1A was functionally investigated in Nore1A-transfected PC12 rat pheochromocytoma cells by fluorescent inhibition of caspase activity and soft agar assays. Significantly suppressed NORE1A and RASSF1A mRNA levels were detected in primary tumours compared with normal adrenal medulla (PNORE1A promoter was not observed in primary tumours. On the other hand, 9% (5/54) of the primary tumours examined showed RASSF1A promoter methylation greater than 20% as detected by Pyrosequencing. Methylation of the RASSF1A promoter was significantly associated with malignant behaviour (PNORE1A and RASSF1A are frequently suppressed in pheochromocytoma and abdominal paraganglioma. Silencing of NORE1A contributes to the transformed phenotype in these tumours.
- Published
- 2007
17. Operation for Primary Hyperparathyroidism: The New versus the Old Order
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Jan Zedenius, R Danielsson, Göran Wallin, Martin Bäckdahl, Hans Jacobsson, H Lindholm, Lars-Ove Farnebo, Bertil Hamberger, S Aarum, E Reihnér, and J Nordenström
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Male ,medicine.medical_specialty ,Decision Making ,Scintigraphy ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,medicine ,Humans ,Minimally Invasive Surgical Procedures ,Radionuclide Imaging ,Pathological ,Aged ,Retrospective Studies ,Ultrasonography ,Aged, 80 and over ,Parathyroidectomy ,Hyperparathyroidism ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,Middle Aged ,Hyperparathyroidism, Primary ,medicine.disease ,Surgery ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Radiology ,business ,Minimally invasive parathyroidectomy ,Neck ,Primary hyperparathyroidism ,Follow-Up Studies - Abstract
Background and Aims: In patients with primary hyperparathyroidism (PHPT), parathyroid imaging is nowadays routinely used for the purpose to perform a focused unilateral minimally invasive operation. The outcome of this new strategy has, however, not been established in randomised trials. Material and Methods: Patients were randomised to either preoperative localisation with sestamibi scintigraphy and ultrasonography (group I) or no preoperative localisation (group II). In group I, a minimally invasive parathyroidectomy was performed in patients in whom both localisation studies were consistent with a single pathological gland, whereas a conventional bilateral neck exploration was performed in cases with negative localisation findings. In group II all patients underwent conventional bilateral neck exploration. Primary outcome measure was normocalcaemia at 6 months postoperatively. Results: In the preoperative localisation group (group I) 23/50 (46%) of the patients could be operated on with the focused operation whereas 26/50 (52%) were operated on by bilateral neck exploration. All patients in the no localisation group (group II; n=50) were operated on with the intended bilateral neck operation. Normocalcaemia was obtained in 96% and 94% in group I and II, respectively. Total (localisation and operative) costs were 21% higher in group I. Conclusions: Routine preoperative localisation, with the intention to perform minimally invasive parathyroidectomy, is not cost effective if concordant results of scintigraphy and ultrasonography are a prerequisite for the focused operation. Less than half of the patients were successfully managed with this strategy, at a higher cost and without obtaining a more favourable clinical outcome.
- Published
- 2007
18. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas
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Hendrik Lehnert, Gunnar Westin, Martin Bäckdahl, Kenko Cupisti, Samuel Backman, Ana Moser, Holger S. Willenberg, Julian C. Y. Ip, Peyman Björklund, Rajani Maharjan, Johan Botling, Henning Dralle, K. Alexander Iwen, Bruce G. Robinson, Stan B. Sidhu, Tobias Åkerström, Cristina D Volpe, Jan Zedenius, Per Hellman, Peter Stålberg, and Martin K. Walz
- Subjects
Adult ,Male ,Cancer Research ,Microarray ,Calcium Channels, L-Type ,Somatic cell ,Endocrinology, Diabetes and Metabolism ,Polymerase Chain Reaction ,Transcriptome ,Immunoenzyme Techniques ,Plasma Membrane Calcium-Transporting ATPases ,Endocrinology ,KCNJ5 ,Hyperaldosteronism ,Biomarkers, Tumor ,Missense mutation ,Humans ,Gene ,Aldosterone ,Aged ,Neoplasm Staging ,Genetics ,Aged, 80 and over ,biology ,Gene Expression Profiling ,Middle Aged ,Prognosis ,Phenotype ,Adrenal Cortex Neoplasms ,Gene expression profiling ,Oncology ,Adrenocortical Adenoma ,Mutation ,Cancer research ,biology.protein ,Female ,Sodium-Potassium-Exchanging ATPase ,Follow-Up Studies - Abstract
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 Ca2+ 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 Ca2+ levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.
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- 2015
19. Cellular DNA Content in Thyroid Tumors
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Torsten Löwhagen, Göran Wallin, Martin Bäckdahl, Gert Auer, Per-Ola Granberg, and Göran Lundell
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Cellular dna ,Chemistry ,Cancer research ,Thyroid tumors - Published
- 2015
20. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
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Fredrika Svahn, C. Christofer Juhlin, Victoria E. Clark, Martin Bäckdahl, Taylor C. Brown, Katsuhito Yasuno, Tobias Carling, Jill C. Rubinstein, Stefano Caramuta, Gerald Goh, Richard P. Lifton, Felix Haglund, Reju Korah, Peter Söderkvist, Murat Gunel, Jacob F Baranoski, Jenny Welander, Oliver Gimm, Kaya Bilguvar, Adam Stenman, and Manju L. Prasad
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Male ,Cancer Research ,Somatic cell ,Adrenal Gland Neoplasms ,Gene Dosage ,Pheochromocytoma ,Biology ,medicine.disease_cause ,Gene dosage ,Cohort Studies ,Sequence Analysis, Protein ,Cell Line, Tumor ,Genetics ,medicine ,Missense mutation ,Humans ,Protein Isoforms ,Exome ,HRAS ,Gene ,Exome sequencing ,Research Articles ,Mutation ,Klinisk medicin ,Neoplasm Proteins ,DNA-Binding Proteins ,Female ,Clinical Medicine ,Transcriptome ,Research Article - Abstract
As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc. Funding Agencies|Stockholm County Council; StratCan, Karolinska Institutet, Stockholm; Agency for Science, Technology and Research, Singapore; Cancer Society in Stockholm, Sweden; Damon Runyon Cancer Research Foundation; Ohse Research Award
- Published
- 2015
21. Predictors of outcome in patients with papillary thyroid carcinoma
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Catharina Larsson, Jan Zedenius, Martin Bäckdahl, Bertil Hamberger, Lars-Ove Farnebo, P. Kjellman, Göran Lundell, and Göran Wallin
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Disease ,Logistic regression ,Outcome (game theory) ,Thyroid carcinoma ,Tumour tissue ,medicine ,Humans ,In patient ,Thyroid Neoplasms ,Favorable outcome ,Radical surgery ,Child ,Aged ,Neoplasm Staging ,Retrospective Studies ,Aged, 80 and over ,business.industry ,General Medicine ,Middle Aged ,Carcinoma, Papillary ,Surgery ,Treatment Outcome ,Oncology ,Thyroidectomy ,Female ,Radiology ,business ,Follow-Up Studies - Abstract
Aim of the study To evaluate prognostic factors with respect to the outcome in a consecutive series of patients with papillary thyroid carcinoma (PTC) treated at the same institution during a 20-year-period, and to evaluate further the predictive ability of outcome of the pTNM, AMES and MACIS prognostic systems in these patients. Materials and methods Two hundred and twenty consecutive patients operated on for primary PTC at the Karolinska Hospital between 1980 and 1999 were examined retrospectively. Patient and tumour characteristics at the time of surgery were compared to the patients' outcomes. Univariate and multiple logistic regression analyses were used to identify independently significant prognostic factors with respect to the outcome. In addition, the classification of the patients according to the pTNM, AMES and MACIS prognostic systems were compared to the outcomes. Results At the end of the follow-up period 201 patients were still alive without disease, 6.5% had died from PTC and 2.5% were alive with persisting disease. In 16 patients, radical surgery could not be performed due to extensive tumour growth and/or distant metastases. Recurrences were detected in 14% of the patients considered as radically operated. The strongest independent predictors for local or distant recurrences and poor clinical outcome were the lack of radical surgery and increasing tumour size. In this investigation MACIS appeared to be the better system, regarding efficacy in predicting the outcome of PTC. Conclusion Removal of all tumour tissue appears most important to a favorable outcome and in our patients MACIS appears the most useful prognostic system taking completeness of resection into account.
- Published
- 2006
22. Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma
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Catharina Larsson, Annabelle L. Fonseca, Gerald Goh, Anna Carinna Suttorp, Taylor C. Brown, Reju Korah, Matthias Haase, Carol Nelson-Williams, Tobias Carling, Ute I. Scholl, David L. Rimm, Martin Bäckdahl, Joseph Schlessinger, James M. Healy, Richard P. Lifton, John D. Overton, John W. Kunstman, Shrikant Mane, Adam Stenman, Manju L. Prasad, Murim Choi, C. Christofer Juhlin, and Anders Höög
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,DNA Copy Number Variations ,Somatic cell ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,medicine.disease_cause ,Biochemistry ,Young Adult ,Endocrinology ,Germline mutation ,Molecular genetics ,medicine ,GNAS complex locus ,Adrenocortical Carcinoma ,Adrenocortical carcinoma ,Humans ,Exome ,Exome sequencing ,Aged ,Genetics ,Mutation ,biology ,JCEM Online: Advances in Genetics ,Biochemistry (medical) ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,Case-Control Studies ,biology.protein ,Female ,Carcinogenesis - Abstract
Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood.To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC.Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC.In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2, and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A, and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs.These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.
- Published
- 2014
23. Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy
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Cecilia Laurell, Magnus Kjellman, Joakim Lundeberg, Janos Geli, Martin Bäckdahl, David Velázquez-Fernández, Peter Nilsson, Anders Höög, Jacob Odeberg, and Bertil Hamberger
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Microarray ,IGFBP3 ,Down-Regulation ,Malignancy ,Complementary DNA ,Adrenocortical Carcinoma ,Image Processing, Computer-Assisted ,medicine ,Humans ,Gene ,Aged ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,biology ,Cadherin ,Gene Expression Profiling ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,Up-Regulation ,ALDH1A1 ,Gene expression profiling ,Adrenocortical Adenoma ,biology.protein ,Cancer research ,Female ,Surgery ,Follow-Up Studies - Abstract
Background Distinguishing between adrenocortical adenomas and carcinomas is often difficult. Our aim was to investigate the differences in transcriptional profiles between benign and malignant adrenocortical neoplasms using complementary DNA microarray techniques. Methods We studied 7 patients with adrenocortical carcinomas and 13 with adenomas. Histopathology was reviewed in all patients; clinical follow-up was at least 1 year. Hybridizations were performed in duplicate against RNA reference. Expression levels were analyzed in the R environment for statistical computing with the use of aroma, limma, statistics, and class packages. Results Transcriptional profiles were homogeneous among adenomas, while carcinomas were much more heterogeneous. Hierarchical clustering and self-organizing maps could separate clearly carcinomas from adenomas. Among genes that were most significantly upregulated in carcinomas were 2 ubiquitin-related genes (USP4 and UFD1L) and several insulinlike growth factor–related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among genes that were most significantly downregulated in carcinomas were a cytokine gene (CXCL10), several genes related to cell metabolism (RARRES2, ALDH1A1, CYBRD1 and GSTA4), and the cadherin 2 gene (CDH2). Conclusions Through the use of cDNA arrays, adrenocortical adenomas and carcinomas appear to be clearly distinguishable on the basis of their specific molecular signature. The biologic importance of the up- and downregulated genes is yet to be determined.
- Published
- 2005
24. MicroRNA expression patterns associated with hyperfunctioning and non-hyperfunctioning phenotypes in adrenocortical adenomas
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Jan Zedenius, Martin Bäckdahl, Deniz M. Ozata, Catharina Larsson, Weng-Onn Lui, Stefano Caramuta, Anders Höög, David Velázquez-Fernández, and Ming Lu
- Subjects
Adult ,Male ,medicine.medical_specialty ,Microarray ,Adenoma ,Adolescent ,Hydrocortisone ,Endocrinology, Diabetes and Metabolism ,Biology ,Gene mutation ,Adrenocortical adenoma ,Cohort Studies ,Young Adult ,Endocrinology ,Internal medicine ,microRNA ,medicine ,Humans ,Aldosterone ,Aged ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Aged, 80 and over ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,General Medicine ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,stomatognathic diseases ,MicroRNAs ,Significance analysis of microarrays ,Adrenocortical Adenoma ,Adrenal Cortex ,Female - Abstract
BackgroundThe adrenocortical adenoma (ACA) entity includes aldosterone-producing adenoma (APA), cortisol-producing adenoma (CPA), and non-hyperfunctioning adenoma (NHFA) phenotypes. While gene mutations and mRNA expression profiles have been partly characterized, less is known about the alterations involving microRNA (miRNA) expression.AimTo characterize miRNA expression profile in relation to the subtypes of ACAs.Subjects and methodsmiRNA expression profiles were determined in 26 ACAs (nine APAs, ten CPAs, and seven NHFAs) and four adrenal references using microarray-based screening. Significance analysis of microarrays (SAM) was carried out to identify differentially expressed miRNAs between ACA and adrenal cortices or between tumor subtypes. Selected differentially expressed miRNAs were validated in an extended series of 43 ACAs and ten adrenal references by quantitative RT-PCR.ResultsAn hierarchical clustering revealed separate clusters for APAs and CPAs, while the NHFAs were found spread out within the APA/CPA clusters. When NHFA was excluded, the clustering analysis showed a better separation between APA and CPA. SAM analysis identified 40 over-expressed and three under-expressed miRNAs in the adenomas as compared with adrenal references. Fourteen miRNAs were common among the three ACA subtypes. Furthermore, we found specific miRNAs associated with different tumor phenotypes.ConclusionThe results suggest that miRNA expression profiles can distinguish different subtypes of ACA, which may contribute to a deeper understanding of ACA development and potential therapeutics.
- Published
- 2014
25. Role of SDHAF2 and SDHD in von Hippel-Lindau associated pheochromocytomas
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Johan Kugelberg, Francesca Schiavi, Peter Söderkvist, Catharina Larsson, Hartmut P. H. Neumann, Patricia L. M. Dahia, Martin Bäckdahl, Jenny Welander, Ambrogio Fassina, Oliver Gimm, and Giuseppe Opocher
- Subjects
Genetic Markers ,endocrine system ,Pathology ,medicine.medical_specialty ,von Hippel-Lindau Disease ,endocrine system diseases ,Genotyping Techniques ,Adrenal Gland Neoplasms ,Mutation, Missense ,Loss of Heterozygosity ,Pheochromocytoma ,urologic and male genital diseases ,Cohort Studies ,Mitochondrial Proteins ,medicine ,Biomarkers, Tumor ,Humans ,Promoter Regions, Genetic ,neoplasms ,business.industry ,Klinisk medicin ,Sequence Analysis, DNA ,Von hippel lindau ,Vascular surgery ,DNA Methylation ,female genital diseases and pregnancy complications ,Cardiac surgery ,Surgery ,Succinate Dehydrogenase ,medicine.anatomical_structure ,Cardiothoracic surgery ,SDHD ,Clinical Medicine ,business ,Adrenal medulla ,Abdominal surgery - Abstract
Background Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. Materials and methods Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. Results and conclusions LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p less than 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.
- Published
- 2014
26. In vitro release of aldosterone and cortisol in human adrenal adenomas correlates to mRNA expression of steroidogenic enzymes for genes CYP11B2 and CYP17
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Anna Wedell, Martin Bäckdahl, Lars Grimelius, Marja Thorén, Ulla Enberg, Staffan Gröndal, Bertil Hamberger, Magnus Kjellman, and Lars-Ove Farnebo
- Subjects
Adult ,Male ,medicine.medical_specialty ,Hydrocortisone ,Adenoma ,Molecular Probe Techniques ,In Vitro Techniques ,chemistry.chemical_compound ,Primary aldosteronism ,Zona fasciculata ,Internal medicine ,Hyperaldosteronism ,medicine ,Cytochrome P-450 CYP11B2 ,Humans ,RNA, Messenger ,Steroid 11-beta-hydroxylase ,Aldosterone ,Cushing Syndrome ,In Situ Hybridization ,Aged ,business.industry ,Adrenal cortex ,Steroid 17-alpha-Hydroxylase ,Middle Aged ,medicine.disease ,Adrenal Cortex Neoplasms ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Zona glomerulosa ,Adrenocortical Adenoma ,Steroid 11-beta-Hydroxylase ,Female ,Surgery ,business - Abstract
Adenomas of the adrenal cortex cause different disorders depending on the main steroid synthesized and released. The aim of this research is to increase our understanding of the pathophysiology of steroidogenesis in adrenocortical disorders by comparing the release of steroids from adrenocortical adenomas in vitro with the messenger RNA (mRNA) expression of steroid synthesizing enzymes. Fourteen patients with adrenal tumors were included in the present study; nine were diagnosed with primary aldosteronism and three with Cushing's syndrome. Two patients had an adrenal tumor discovered on computed tomography (CT) during workup for an unrelated disease. Serum cortisol, plasma aldosterone, and urinary catecholamines were normal. Tissue was taken for in vitro steroid release, and aldosterone and cortisol in the medium after a 1-hour incubation were determined. Oligonucleotide probes with sequences complementary to mRNAs encoding for the steroid synthesizing enzymes 11 beta-hydroxylase (CYP11B1), 18-hydroxylase (CYP11B2), 17 alpha-hydroxylase (CYP17), and 21-hydroxylase (CYP21) were synthesized (Genset, Paris, France) and in situ hybridization was performed. Moderate expression of CYP11B2 and low expression of CYP11B1 were seen in the zona glomerulosa. The zona fasciculata of the control adrenals expressed a high signal of CYP11B1, whereas the expression of CYP11B2 was very low. There was considerable variation in aldosterone release from the aldosteronomas, whereas the tumors from the Cushing patients showed no detectable release of aldosterone. In contrast, tumors from patients with primary aldosteronism, Cushing's syndrome, and no hyperfunction all had the ability to synthesize and release cortisol in vitro. The highest cortisol release was found in tumors from patients with Cushing's syndrome, but also the nonhyperfunctioning tumors and some of the aldosteronomas released significant amounts of cortisol. The two patients with highest release of aldosterone in vitro showed the highest expression of CYP11B2 and the lowest expression of CYP11B1 and CYP17. The remaining aldosteronomas had low expression of CYP11B2, similar to the two other groups. Expression of CYP11B1 was high as expected in the Cushing adenomas, but also the two nonhyperfunctioning tumors and some of the aldosteronomas showed a moderate expression. Adenomas from Cushing's syndrome, nonhyperfunctioning adenomas, and some of the aldosterone-producing adenomas had moderate to high expression of CYP17. This paper presents new means for functional characterization of adrenocortical tumors. Diagnosis of an aldosteronoma is often difficult, and with the advent of these methods it is possible to determine the functional capacity of a tumor, once it is removed. This is of special interest if the patient remains hypertensive postoperatively, and it is not clear whether the patient indeed had a functioning tumor.
- Published
- 2001
27. Gelatinase A, Membrane Type 1 Matrix Metalloproteinase, and Extracellular Matrix Metalloproteinase Inducer mRNA Expression: Correlation with Invasive Growth of Breast Cancer
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Kristina Dalberg, Magnus Kjellman, Martin Bäckdahl, Ulla Enberg, and Elina Eriksson
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,Stromal cell ,Gelatinase A ,Breast Neoplasms ,Adenocarcinoma ,Matrix metalloproteinase ,Metastasis ,Breast cancer ,Antigens, CD ,Antigens, Neoplasm ,medicine ,Carcinoma ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Neoplasm Metastasis ,In Situ Hybridization ,Aged ,Membrane Glycoproteins ,business.industry ,Carcinoma in situ ,Middle Aged ,medicine.disease ,Basigin ,Matrix Metalloproteinase 2 ,Female ,Surgery ,Matrix Metalloproteinase 1 ,Neoplasm Recurrence, Local ,Breast carcinoma ,business - Abstract
Invasive breast cancer varies widely in biologic aggressiveness, from fairly indolent tumors to rapidly disseminating carcinomas. Matrix metalloproteinases have enzymatic activity and assist in tumor invasion by degrading basement membranes and extracellular matrix. The extracellular matrix metalloproteinase inducer EMMPRIN is thought to stimulate fibroblasts to produce the zymogen pro-gelatinase A. The membrane type 1-matrix metalloproteinase (MT1-MMP) is thought to assist in tumor invasion and metastasis by activating pro-gelatinase A, which shows enhanced expression in various tumors. Overexpression of gelatinase A has shown to correlate with a malignant phenotype in many tumor forms. The aim of the study was to investigate the mRNA expression pattern of MT1-MMP, gelatinase A, and EMMPRIN in breast tumors. Formalin-fixed paraffin-embedded breast tissue samples from 18 patients operated on with breast-conserving surgery for invasive breast carcinoma20 mm between 1977 and 1985 were analyzed using the mRNA in situ hybridization technique. Most of the patients were node-negative (15/18) and underwent postoperative irradiation to the breast (16/18). The median age at diagnosis was 52 years (21-83 years). At the time of the study 11 patients were alive, 4 without recurrence; 7 patients had been operated for ipsilateral breast tumor recurrences, and 2 had distant metastases. The median follow-up was 112 months (102-193 months). Seven patients died of disseminated breast cancer; their median follow-up was 43 months (22-116 months). (35)S-labeled antisense and sense mRNA probes transcribed from linearized plasmids containing cDNA for the matrix metalloproteinases gelatinase A and MT1-MMP and the glycoprotein EMMPRIN were hybridized to 5 microm paraffin-embedded tissue sections. Several invasive carcinomas were surrounded by normal tissue and carcinoma in situ lesions. Gelatinase A, MT1-MMP, and EMMPRIN mRNA expression were detected in all of the carcinomas. The gelatinase A mRNA expression was mainly localized to stromal cells at moderate to high levels surrounding the invading carcinoma cells but was also seen in single cells at low levels in in situ lesions and in some normal glandular cells. MT1-MMP and EMMPRIN were expressed in all of the carcinomas and were mainly localized to tumor cells; but they were also seen to some extent in single cells at low levels in in situ lesions and in normal glandular cells. No differences in levels of expression for gelatinase A, MT1-MMP, or EMMPRIN were seen in patients who survived compared to patients who died from metastatic disease. The co-expression of gelatinase A, MT1-MMP, and EMMPRIN mRNA in invasive breast carcinoma supports the theory that these proteins interact and are important for the invasive phenotype in breast carcinoma. Hence EMMPRIN may be a central factor for stimulation of gelatinase A activation. Specific inhibition for individual MMP members could in the future be target-specific events in breast tumor progression. Inhibition of EMMPRIN could be such a target.
- Published
- 2000
28. Comparative Genomic Hybridization Reveals Frequent Losses of Chromosomes 1p and 3q in Pheochromocytomas and Abdominal Paragangliomas, Suggesting a Common Genetic Etiology
- Author
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Nikolai Goncharov, Bin Tean Teh, Elisabeth Edström, Catharina Larsson, Martin Bäckdahl, Anders Höög, Magnus Kjellman, Ritva Karhu, Brita Nord, and Eija Mahlamäki
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Adolescent ,DNA Mutational Analysis ,Adrenal Gland Neoplasms ,Pheochromocytoma ,Biology ,Pathology and Forensic Medicine ,Paraganglioma ,Multiple Endocrine Neoplasia Type 1 ,medicine ,Humans ,Abdominal Neoplasms ,Multiple endocrine neoplasia ,Aged ,Cytogenetics ,Nucleic Acid Hybridization ,Chromosome ,Middle Aged ,medicine.disease ,Chromosome 3 ,Chromosomes, Human, Pair 1 ,Female ,Chromosomes, Human, Pair 3 ,Gene Deletion ,Regular Articles ,Comparative genomic hybridization - Abstract
Pheochromocytomas and abdominal paragangliomas are rare, catecholamine-producing tumors that arise from the chromaffin cells derived from the neural crest. We used comparative genomic hybridization (CGH) to screen for copy number changes in 23 pheochromocytomas and 11 abdominal paragangliomas. The pattern of copy number changes was similar between pheochromocytomas and paragangliomas, with the most consistent finding being loss of 1cen-p31, which was detected in 28/34 tumors (82%). Losses were also found on 3q22–25 (41%), 11p (26%), 3p13–14 (24%), 4q (21%), 2q (15%), and 11q22–23 (15%), and gains were detected on 19p (26%), 19q (24%), 17q24-qter (21%), 11cen-q13 (15%), and 16p (15%). Losses of 1p and 3q were detected in the majority of tumors, whereas gains of 19p and q, 17q, and 16p were seen only in tumors with six or more CGH alterations. This progression of genetic events did not correspond with the conversion to a malignant phenotype. CGH alterations involving chromosome 11 were more frequent in the malignant tumors, compared with the benign tumors (9/12 versus 3/16). In summary, we propose that pheochromocytomas and abdominal paragangliomas, which share many clinical features, also have a common genetic origin and that the loss of 1cen-p31 represents an early and important event in tumor development.
- Published
- 2000
29. No overrepresentation of congenital adrenal hyperplasia in patients with adrenocortical tumours
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Anna Wedell, Catharina Larsson, Martin Bäckdahl, Mikael Holst, Lars-Ove Farnebo, and Magnus Kjellman
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education.field_of_study ,medicine.medical_specialty ,Pathology ,Mutation ,business.industry ,Adrenal cortex ,Endocrinology, Diabetes and Metabolism ,Population ,Heterozygote advantage ,Autopsy ,Hyperplasia ,Adrenal Cortex Neoplasm ,medicine.disease ,medicine.disease_cause ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,medicine ,Congenital adrenal hyperplasia ,education ,business - Abstract
OBJECTIVE The development and progression of sporadic adrenocortical tumours are poorly understood. In autopsy studies adrenocortical tumours are found in between 2 and 9% of the general population. In congenital adrenal hyperplasia (CAH), decreased production of cortisol leads to increased secretion of ACTH from the pituitary, resulting in hyperplasia of the adrenals. More than 95% of all cases of CAH are due to steroid 21-hydroxylase deficiency, resulting from mutations in the CYP21 gene. In subjects homozygous and heterozygous for CYP21 mutations, adrenocortical tumours have been found in a high frequency compared to the general population, suggesting that chronic ACTH stimulation may play a role in the development of this tumour form. In order to test whether mild undiagnosed CAH is a common predisposing factor, we screened 27 patients with sporadic adrenocortical tumours for CYP21 mutations. DESIGN A retrospective study. PATIENTS We screened 27 patients with sporadic adrenocortical tumours, representing both benign and malignant as well as hormonally active and silent lesions. MEASUREMENTS Mutation analyses of the CYP21 gene was performed by allele-specific PCR on high molecular weight DNA. The method used detects the nine CYP21 mutations that are responsible for 95% of all disease-causing alleles in CAH. RESULTS No mutations were detected in any of the 23 DNA samples that were prepared from leucocytes. In 4 cases where no leucocyte DNA was available, tumour tissue was analysed. In one of these tumours, two CYP21 mutations, V281 L and L307insT, were found in heterozygous form. CONCLUSION Our data indicate that mild undiagnosed congenital adrenal hyperplasia is not a common underlying factor predisposing to adrenocortical tumours, at least not in the Swedish population.
- Published
- 1999
30. Genotyping of Adrenocortical Tumors: Very Frequent Deletions of the MEN1 Locus in 11q13 and of a 1-Centimorgan Region in 2p161
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Steven G. Gray, Magnus Kjellman, Anders Höög, Lars-Ove Farnebo, Martin Bäckdahl, Catharina Larsson, Leyla Roshani, Bin Tean Teh, Mikael Holst, and Olli-Pekka Kallioniemi
- Subjects
Genetics ,medicine.medical_specialty ,endocrine system diseases ,Tumor suppressor gene ,Adenoma ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Locus (genetics) ,Biology ,medicine.disease ,Biochemistry ,Loss of heterozygosity ,Endocrinology ,Internal medicine ,medicine ,MEN1 Gene Mutation ,MEN1 ,Multiple endocrine neoplasia ,Carney complex - Abstract
To identify chromosomal regions that may contain loci for tumor suppressor genes involved in adrenocortical tumor development, a panel of 60 tumors (39 carcinomas and 21 adenomas) were screened for loss of heterozygosity. Although the vast majority of loss of heterozygosity (LOH) were detected in the carcinomas and involved chromosomes 2, 4, 11, and 18, only few were found in the adenomas. Therefore, 2 loci that harbor the familial cancer syndromes Carney complex in 2p16 and the multiple endocrine neoplasia type 1 gene in 11q13 were further studied in 27 (13 carcinomas and 14 adenomas) of the 60 tumors. Detailed analysis of the 2p16 region mapped a minimal area of overlapping deletions to a 1-centimorgan region, which is separate from the Carney complex locus. LOH for a microsatellite marker (PYGM), very close to the MEN1 gene, was detected in all 8 informative carcinomas (100%) and in 2 of 14 adenomas. Of the 27 cases analyzed in detail, 13 cases (11 carcinomas and 2 adenomas) showed LOH on chromosome 11 and was therefore selected for MEN1 gene mutation analysis. In 6 cases a common polymorphism (Asp418Asp) was found, but no mutation was detected. In conclusion, our data indicate the existence of tumor suppressor genes at multiple chromosomal locations, whose inactivations are involved in the development of adrenocortical carcinomas. Loss of genetic material from 2p16 was strongly associated with the malignant phenotype, as it was seen in almost all carcinomas but not in any of the adenomas. LOH in 11q13 also occurred frequently in the carcinomas, but was not associated with a MEN1 mutation, suggesting the involvement of a different tumor suppressor gene on this chromosome.
- Published
- 1999
31. Tumor-Specific Decreased Expression of Calcium Sensing Receptor Messenger Ribonucleic Acid in Sporadic Primary Hyperparathyroidism1
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Martin Schalling, Lars-Ove Farnebo, Lars Grimelius, Ulla Enberg, Martin Bäckdahl, Catharina Larsson, and Filip Farnebo
- Subjects
medicine.medical_specialty ,endocrine system diseases ,Adenoma ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,chemistry.chemical_element ,In situ hybridization ,Biology ,Calcium ,Biochemistry ,Endocrinology ,Internal medicine ,medicine ,Messenger RNA ,Hyperparathyroidism ,Biochemistry (medical) ,Parathyroid chief cell ,medicine.disease ,digestive system diseases ,stomatognathic diseases ,chemistry ,Calcium-sensing receptor ,human activities ,hormones, hormone substitutes, and hormone antagonists ,Primary hyperparathyroidism - Abstract
Secretion of PTH is regulated by extracellular calcium via calcium receptors (CaR) on the parathyroid cell surface. Recent studies have shown a decreased expression of CaR messenger RNA (mRNA) and CaR protein in pathological parathyroids. We studied the expression of CaR mRNA in pairs of adenoma and adenoma-associated normal gland from the same patients (n = 17) and in biopsies of normal parathyroid glands of normocalcemic subjects (n = 4) using in situ hybridization with oligonucleotide probes on frozen sections. No down-regulation of CaR mRNA caused by hypercalcemia could be demonstrated in the normal adenoma-associated parathyroids when compared with the normal parathyroids of normocalcemic subjects. In contrast, CaR mRNA in the adenomas was significantly reduced to 64% (median; range 41-98) of the corresponding normal adenoma-associated glands. No correlation was seen between CaR mRNA in the adenoma and preoperative serum calcium, PTH, or weight of the adenoma. Loss of heterozygosity studies were performed on adenomas using markers for the locus of the CaR gene on chromosome 3q. No allelic loss was demonstrated, excluding allelic loss as the cause for decreased CaR mRNA expression in the adenomas. It is concluded that the lowered levels of CaR mRNA in parathyroid adenomas may contribute to the increased set point of PTH secretion. In large adenomas the increased cell mass seems to be more important for the increased secretion of PTH.
- Published
- 1997
32. Deletions of the long arm of chromosome 10 in progression of follicular thyroid tumors
- Author
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Martin Bäckdahl, Catharina Larsson, Anders Höög, Jan Zedenius, Ann Svensson, Judith V.M.G. Bovée, and Göran Wallin
- Subjects
medicine.medical_specialty ,endocrine system diseases ,Adenoma ,Locus (genetics) ,Biology ,Thyroid carcinoma ,Loss of heterozygosity ,Internal medicine ,Adenocarcinoma, Follicular ,Genetics ,medicine ,Humans ,Thyroid Neoplasms ,Genetics (clinical) ,Chromosomes, Human, Pair 10 ,Thyroid ,Chromosome Mapping ,Chromosome ,DNA, Neoplasm ,medicine.disease ,digestive system diseases ,stomatognathic diseases ,Endocrinology ,medicine.anatomical_structure ,Chromosome 3 ,Genetic marker ,Cancer research ,Gene Deletion - Abstract
Previous studies of follicular thyroid tumors have shown loss of heterozygosity (LOH) on the short arm of chromosome 3 in carcinomas, and on chromosome 10 in atypical adenomas and carcinomas, but not in common adenomas. We studied LOH on these chromosomal arms in 15 follicular thyroid carcinomas, 19 atypical follicular adenomas and 6 anaplastic (undifferentiated) carcinomas. Deletion mapping of chromosome 10 using 15 polymorphic markers showed that 15 (37.5%) of the tumors displayed LOH somewhere along the long arm. Thirteen of these tumors showed deletions involving the telomeric part of chromosome 10q, distal to D1OS 187. LOH on chromosome 3p was found in 8 (20%) cases. Seven of these also showed LOH on chromosome 10q. In eight cases LOH was seen on chromosome 10q but not 3p. In comparison, the retinoblastoma gene locus at chromosome 13q showed LOH in 22% of the tumors. Most of these also had deletions on chromosome 10q. The results indicate that a region at the telomeric part of 10q may be involved in progression of follicular thyroid tumors.
- Published
- 1996
33. Stromal Fibroblasts Adjacent to Invasive Thyroid Tumors: Expression of Gelatinase A But Not Stromelysin 3 mRNA
- Author
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Martin Bäckdahl, Catharina Larsson, Jan Zedenius, Göran Wallin, Lars Grimelius, Mona Ståhle-Bäckdahl, and Ulla Enberg
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Gelatinase A ,In situ hybridization ,Adenocarcinoma ,Extracellular matrix ,Stroma ,Matrix Metalloproteinase 11 ,Adenocarcinoma, Follicular ,Adenoma, Oxyphilic ,Humans ,Medicine ,RNA, Messenger ,Thyroid Neoplasms ,Fibroblast ,In Situ Hybridization ,Aged ,Aged, 80 and over ,Basement membrane ,business.industry ,Carcinoma ,Thyroid ,Metalloendopeptidases ,Fibroblasts ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Gelatinases ,Matrix Metalloproteinase 2 ,Female ,Surgery ,business - Abstract
Thyroid tumors vary widely in biologic behavior, they range from benign adenomas to rapidly growing anaplastic carcinomas. Among thyroid neoplasms, the follicular tumor is especially suited as a model for studies of tumor cell invasion; the distinction between adenomas and carcinomas relies mainly on the presence of capsular and vascular invasion. Matrix metalloproteinases play an important role in tumor cell invasion, as they are able to degrade basement membrane and extracellular matrix components. Twenty-nine thyroid tumors of varying type and aggressiveness were selected for analysis of relative molecular weight 72,000-dalton type IV collagenase (gelatinase A) expression by mRNA in situ hybridization. Strong gelatinase A mRNA expression was seen in 10 of 14 follicular carcinomas, in none of six follicular adenomas, in all four anaplastic carcinomas, and in four of five papillary carcinomas. The expression was restricted to fibroblasts in the stroma adjacent or close to invading tumor cells. Twelve of the tumors were also investigated for expression of stromelysin 3 mRNA, no expression of which was detected in any tumor. The findings suggest that gelatinase A contributes to the invasive process and spread of aggressive thyroid tumors.
- Published
- 1996
34. Allelotyping of follicular thyroid tumors
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Lars Grimelius, Martin Bäckdahl, Göran Wallin, Catharina Larsson, Jan Zedenius, Anders Höög, Göran Lundell, and Ann Svensson
- Subjects
Heterozygote ,endocrine system ,endocrine system diseases ,Locus (genetics) ,DNA, Satellite ,Biology ,Polymerase Chain Reaction ,Follicular cell ,Loss of heterozygosity ,Adenocarcinoma, Follicular ,Follicular phase ,Genetics ,Carcinoma ,medicine ,Chromosomes, Human ,Humans ,Genes, Tumor Suppressor ,Thyroid Neoplasms ,Alleles ,Genetics (clinical) ,Repetitive Sequences, Nucleic Acid ,Polymorphism, Genetic ,Epithelioma ,Thyroid ,Chromosome ,DNA, Neoplasm ,medicine.disease ,medicine.anatomical_structure ,Cancer research ,Chromosome Deletion - Abstract
To elucidate further the genetic mechanisms for follicular thyroid tumor development and progression, we allelotyped follicular thyroid tumors and other thyroid lesions from 92 patients. In general, a low frequency of loss of heterozygosity (LOH) was found, the highest being for chromosomes 3q, 10q, 11p, 11q, 13q, and 22q (10%-15%). However, detailed study of LOH of these chromosome arms with regard to the different histopathological diagnoses indicates that a locus on chromosome 10q may be involved in follicular thyroid tumor progression. In addition, the majority of Hürthle cell adenomas showed LOH on either chromosome 3q or 18q, in contrast to the other tumor types. This discrepancy in genetic alterations may contribute to the divergent clinical features occurring in these tumors.
- Published
- 1995
35. Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter
- Author
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Henning Dralle, Pier Francesco Alesina, Gunnar Westin, Peter Stålberg, Myriam Decaussin, Bruce G. Robinson, Kurt Werner Schmid, Jean-Louis Peix, Martin K. Walz, Peyman Björklund, Julian C. Y. Ip, Göran Åkerström, Alberto Delgado Verdugo, Hendrik Lehnert, Richard P. Lifton, Johan Botling, K. Alexander Iwen, Wolfgang Saeger, Alfred C. Feller, Jean-Louis Kraimps, Martin Anlauf, Patsy S. Soon, Murim Choi, Wolfram T. Knoefel, Stefano Caramuta, Lee F. Starker, Martin Bäckdahl, Holger S. Willenberg, Tobias Carling, Kenko Cupisti, Joakim Crona, Bo Wängberg, Pierre Levillain, Jan Zedenius, Per Hellman, Stan B. Sidhu, and Tobias Åkerström
- Subjects
Male ,Familial hyperaldosteronism ,Medicin och hälsovetenskap ,DNA Mutational Analysis ,Medizin ,lcsh:Medicine ,medicine.disease_cause ,Medical and Health Sciences ,Cohort Studies ,chemistry.chemical_compound ,Primary aldosteronism ,Endocrinology ,Mutation Rate ,Basic Cancer Research ,Endocrine Surgery ,lcsh:Science ,Aldosterone ,Mutation ,Sex Characteristics ,Multidisciplinary ,biology ,Middle Aged ,Surgical Oncology ,Oncology ,Adrenocortical Adenoma ,Medicine ,Female ,Sequence Analysis ,Research Article ,Adult ,medicine.medical_specialty ,Adolescent ,Young Adult ,Germline mutation ,Internal medicine ,KCNJ5 ,medicine ,Humans ,Genetic Testing ,Biology ,Aged ,Clinical Genetics ,Base Sequence ,Point mutation ,lcsh:R ,Computational Biology ,Neuroendocrinology ,medicine.disease ,Adrenal Cortex Neoplasms ,chemistry ,biology.protein ,Adrenal Cortex ,lcsh:Q ,Surgery ,Carcinogenesis ,Population Genetics - Abstract
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
- Published
- 2012
36. Haemodynamic effects of pneumoperitoneum and the influence of posture during anaesthesia for laparoscopic surgery
- Author
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Martin Bäckdahl, A. von Rosen, S. Odeberg, P. Gannedahl, T. Svenberg, Olle Ljungqvist, and Alf Sollevi
- Subjects
Adult ,Male ,Increased pulmonary capillary wedge pressure ,Insufflation ,Mean arterial pressure ,Adolescent ,Central Venous Pressure ,Posture ,Blood Pressure ,Pulmonary Artery ,Pneumoperitoneum ,Afterload ,Heart Rate ,Tidal Volume ,Ventricular Pressure ,medicine ,Humans ,Pulmonary Wedge Pressure ,Cardiac Output ,Cardiopulmonary disease ,business.industry ,Respiration ,Hemodynamics ,Central venous pressure ,General Medicine ,Carbon Dioxide ,Middle Aged ,medicine.disease ,Oxygen ,Preload ,Anesthesiology and Pain Medicine ,Cholecystectomy, Laparoscopic ,Anesthesia ,Anesthesia, Intravenous ,Female ,Vascular Resistance ,business ,Pneumoperitoneum, Artificial - Abstract
The laparoscopic operating technique is being applied increasingly to a variety of intra-abdominal operations. Intra-abdominal gas insufflation, i.e. pneumoperitoneum (PP), is then used to allow surgical access. The haemodynamic effects of PP in combination with different body positions have not been fully examined. Eleven patients without signs of cardiopulmonary disease were studied before and during laparoscopic cholecystectomy under propofol-fentanyl anaesthesia with controlled ventilation. Swan-Ganz and radial arterial catheterization were used to determine haemodynamic data in the horizontal position, with a 15-20 degree head-down tilt and a 15-20 degree head-up tilt. The measurements were repeated after insufflation of carbon dioxide to an intraabdominal pressure of 11-13 mmHg, as well as during surgery. The ventricular filling pressures of the heart were strictly dependent on body position. PP in the horizontal position increased pulmonary capillary wedge pressure by 32% (P < 0.01), central venous pressure by 58% (P < 0.01), and mean arterial pressure by 39% (P < 0.01). When PP was combined with a head-down tilt, there was a further increase in filling pressures by approximately 40% (P < 0.01), while the reduction in filling pressures during the head-up tilt was counteracted by PP. During PP with a head-up tilt, the filling pressures did not differ from those in the horizontal position without PP. CI showed a certain dependency on filling pressures. It is concluded that PP causes signs of elevated preload and afterload. The combination of PP and a head-up tilt is associated only with signs of an elevated afterload.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
37. Anaplastic carcinoma of the thyroid gland: treatment and outcome over 13 years at one institution
- Author
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Ivan, Segerhammar, Catharina, Larsson, Inga-Lena, Nilsson, Martin, Bäckdahl, Anders, Höög, Göran, Wallin, Theodoros, Foukakis, and Jan, Zedenius
- Subjects
Aged, 80 and over ,Male ,Time Factors ,Carcinoma ,Middle Aged ,Thyroid Carcinoma, Anaplastic ,Combined Modality Therapy ,Survival Analysis ,Treatment Outcome ,Humans ,Female ,Thyroid Neoplasms ,Aged ,Follow-Up Studies ,Retrospective Studies - Abstract
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy of the thyroid gland. Patients at our institution are treated with external radiotherapy up to 46 Gray (Gy) and low-dose doxorubicin prior to surgery. We retrospectively evaluated the outcome of ATC patients over a 13-year period.Clinical, histopathological, and follow-up data for 59 patients diagnosed between 1997 and 2010 were collected and analyzed.Median age at diagnosis was 77 years. Female-male ratio was 2.5:1. Median survival from time of diagnosis was 3.3 months. Thirty-six patients completed the treatment protocol (including surgery), of whom one succumbed due to local tumor growth. In multivariate analysis, the only factor significantly associated with longer survival among operated patients was absence of metastases at diagnosis (P = 0.031). No impact on survival time was found for gender, extent of surgical resection, and absence of extrathyroidal invasion.Despite aggressive treatment, survival rates in ATC patients remain low. Locoregional control is feasible for most patients, underscoring the importance of an intense, multimodal treatment regimen. Further oncological intervention is of crucial importance to achieve a better prognosis for ATC patients.
- Published
- 2011
38. The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma
- Author
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Catharina Larsson, Anders Höög, Weng-Onn Lui, Stefano Caramuta, David Velázquez-Fernández, Deniz M. Ozata, Hong Xie, Martin Bäckdahl, Jan Zedenius, and Pinar Akcakaya
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Microarray ,Adenoma ,Endocrinology, Diabetes and Metabolism ,Cell Growth Processes ,Biology ,Statistics, Nonparametric ,Endocrinology ,Internal medicine ,Puma ,Cell Line, Tumor ,Proto-Oncogene Proteins ,microRNA ,medicine ,Adrenocortical Carcinoma ,Adrenocortical carcinoma ,Humans ,p53 upregulated modulator of apoptosis ,RNA, Neoplasm ,Aged ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Aged, 80 and over ,Reverse Transcriptase Polymerase Chain Reaction ,Regular Papers ,Cancer ,Middle Aged ,medicine.disease ,biology.organism_classification ,Survival Analysis ,Adrenal Cortex Neoplasms ,Gene Expression Regulation, Neoplastic ,stomatognathic diseases ,MicroRNAs ,Oncology ,Cancer research ,biology.protein ,Female ,Apoptosis Regulatory Proteins - Abstract
Adrenocortical carcinoma (ACC) is an aggressive tumor showing frequent metastatic spread and poor survival. Although recent genome-wide studies of ACC have contributed to our understanding of the disease, major challenges remain for both diagnostic and prognostic assessments. The aim of this study was to identify specific microRNAs (miRNAs) associated with malignancy and survival of ACC patients. miRNA expression profiles were determined in a series of ACC, adenoma, and normal cortices using microarray. A subset of miRNAs showed distinct expression patterns in the ACC compared with adrenal cortices and adenomas. Among others, miR-483-3p, miR-483-5p, miR-210, and miR-21 were found overexpressed, while miR-195, miR-497, and miR-1974 were underexpressed in ACC. Inhibition of miR-483-3p or miR-483-5p and overexpression of miR-195 or miR-497 reduced cell proliferation in human NCI-H295R ACC cells. In addition, downregulation of miR-483-3p, but not miR-483-5p, and increased expression of miR-195 or miR-497 led to significant induction of cell death. Protein expression of p53 upregulated modulator of apoptosis (PUMA), a potential target of miR-483-3p, was significantly decreased in ACC, and inversely correlated with miR-483-3p expression. In addition, high expression of miR-503, miR-1202, and miR-1275 were found significantly associated with shorter overall survival among patients with ACC (P values: 0.006, 0.005, and 0.042 respectively). In summary, we identified additional miRNAs associated with ACC, elucidated the functional role of four miRNAs in the pathogenesis of ACC cells, demonstrated the potential involvement of the pro-apoptotic factor PUMA (a miR-483-3p target) in adrenocortical tumors, and found novel miRNAs associated with survival in ACC.
- Published
- 2011
39. Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis
- Author
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Carl E.G. Bruder, Catharina Larsson, Nimrod B Kiss, Jan Komorowski, Göran Åkerström, Robin Andersson, Jan P. Dumanski, Teresita Díaz de Ståhl, Uwe Menzel, Martin Bäckdahl, Michael Brauckhoff, Henning Dralle, Ola Hessman, Gunnar Westin, Arkadiusz Piotrowski, Helena Nord, and Johanna Sandgren
- Subjects
Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Adrenal Gland Neoplasms ,Biology ,Genome ,Loss of heterozygosity ,Paraganglioma ,Endocrinology ,medicine ,Humans ,Gene ,Aged ,Comparative Genomic Hybridization ,Autosome ,Reverse Transcriptase Polymerase Chain Reaction ,Cancer ,Chromosome ,Middle Aged ,medicine.disease ,Oncology ,Mutation ,Female ,Trisomy ,Comparative genomic hybridization ,Genome-Wide Association Study - Abstract
Pheochromocytomas and abdominal paragangliomas are adrenal and extra-adrenal catecholamine-producing tumours. They arise due to heritable cancer syndromes, or more frequently occur sporadically due to an unknown genetic cause. The majority of cases are benign, but malignant tumours are observed. Previous comparative genomic hybridization (CGH) and loss of heterozygosity studies have shown frequent deletions of chromosome arms 1p, 3q and 22q in pheochromocytomas. We applied high-resolution whole-genome array CGH on 53 benign and malignant pheochromocytomas and paragangliomas to narrow down candidate regions as well as to identify chromosomal alterations more specific to malignant tumours. Minimal overlapping regions (MORs) were identified on 16 chromosomes, with the most frequent MORs of deletion (≥32%) occurring on chromosome arms 1p, 3q, 11p/q, 17p and 22q, while the chromosome arms 1q, 7p, 12q and 19p harboured the most common MORs of gain (≥14%). The most frequent MORs (61–75%) in the pheochromocytomas were identified at 1p, and the four regions of common losses encompassed 1p36, 1p32–31, 1p22–21 and 1p13. Tumours that did not show 1p loss generally demonstrated aberrations on chromosome 11. Gain of chromosomal material was significantly more frequent among the malignant cases. Moreover, gain at 19q, trisomy 12 and loss at 11q were positively associated with malignant pheochromocytomas, while 1q gain was commonly observed in the malignant paragangliomas. Our study revealed novel and narrow recurrent chromosomal regions of loss and gain at several autosomes, a prerequisite for identifying candidate tumour suppressor genes and oncogenes involved in the development of adrenal and extra-adrenal catecholamine-producing tumours.
- Published
- 2010
40. Follicular tumors of the thyroid gland: Diagnosis, clinical aspects and nuclear DNA analysis
- Author
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Göran Wallin, Jan Zedenius, Martin Bäckdahl, Gert Auer, Ursula Falkmer, Lars Grimelius, and Göran Lundell
- Subjects
Adenoma ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Adenocarcinoma ,Follicular phase ,Image Processing, Computer-Assisted ,medicine ,Humans ,Prospective Studies ,Thyroid Neoplasms ,Prospective cohort study ,Aged ,Aged, 80 and over ,business.industry ,Thyroid ,DNA, Neoplasm ,Middle Aged ,Flow Cytometry ,medicine.disease ,stomatognathic diseases ,medicine.anatomical_structure ,Cardiothoracic surgery ,Oxyphil cell (pathology) ,Image Cytometry ,Female ,Surgery ,business ,Abdominal surgery - Abstract
From 1985 to 1990, 169 patients underwent surgery for follicular thyroid tumors at the Department of Surgery, Karolinska Hospital, Stockholm, Sweden. Nine of the patients had tumors which were diagnosed as follicular carcinoma, 4 of whom had recurrences in the neck region. In 6 of the patients the carcinomas were diagnosed as widely invasive and in 3 patients as minimally invasive. Of the 160 patients with follicular adenomas, 21 adenomas were of oxyphil type ("Hürthle" adenomas), 17 adenomas were diagnosed as "atypical", and 6 adenomas were classified as being both "atypical" and having oxyphil cell differentiation. The nuclear DNA content was measured with image cytometry and/or flow cytometry. Six of the 9 carcinomas were euploid and 3 were aneuploid. In the adenoma group, 32 (20%) were aneuploid. Thus 38% of all adenomas showed atypical cellular features, oxyphil cell differentiation, and/or aneuploid nuclear DNA pattern. None of the patients with adenomas have shown any sign of recurrence. In the present prospective study, the nuclear DNA content could not discriminate between a benign and a malignant follicular tumor, and was of limited value in predicting prognosis in the patients with follicular carcinoma. Still, the best way to establish a diagnosis and to predict prognosis is to surgically remove the follicular tumor for a proper histopathological examination.
- Published
- 1992
41. Preoperative 99Tc(m)-sestamibi scintigraphy with SPECT localizes most pathologic parathyroid glands
- Author
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Hans Jacobsson, Magnus Kjellman, Evangelos Chandanos, Martin Bäckdahl, Viljam Lindqvist, and Göran Wallin
- Subjects
Parathyroidectomy ,Adult ,Male ,Technetium Tc 99m Sestamibi ,medicine.medical_specialty ,medicine.medical_treatment ,Single-photon emission computed tomography ,Scintigraphy ,Sensitivity and Specificity ,Parathyroid Glands ,Young Adult ,Predictive Value of Tests ,medicine ,Humans ,Aged ,Aged, 80 and over ,Tomography, Emission-Computed, Single-Photon ,Hyperparathyroidism ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,Hyperparathyroidism, Primary ,Cardiothoracic surgery ,Predictive value of tests ,Surgery ,Female ,Radiology ,Radiopharmaceuticals ,business ,Primary hyperparathyroidism ,Abdominal surgery - Abstract
Surgery is the only curative treatment for primary hyperparathyroidism. Focused surgical techniques are being practiced with increasing frequency. Preoperative imaging, such as scintigraphy, is a prerequisite for focused surgery. There is controversy about which preoperative imaging method should be used. The sensitivity reported for parathyroid scintigraphy varies considerably. This study was designed to determine the accuracy of the preoperative imaging routinely used at our institution. This retrospective study included consecutive patients who underwent a routine dual-phase sestamibi-SPECT (single photon emission computed tomography) scintigraphy and subsequent operation with follow-up. Scintigraphy results were evaluated by comparing the results to surgical findings and histopathology. Two hundred and sixty-four individuals entered the study. Sensitivity for scintigraphy was 84%, specificity 91%, positive predictive value 91%, and negative predictive value 84%. Sestamibi-SPECT scintigraphy is a sensitive preoperative modality with high positive predictive value. Scintigraphy is a good indicator for when to perform a focused surgical approach and could often correctly guide the actual operation.
- Published
- 2009
42. Global and regional CpG methylation in pheochromocytomas and abdominal paragangliomas: association to malignant behavior
- Author
-
Nimrod B Kiss, Martin Bäckdahl, Catharina Larsson, Mohsen Karimi, Jia-Jing Lee, Janos Geli, and Tomas J. Ekström
- Subjects
Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,Adrenal Gland Neoplasms ,Pheochromocytoma ,CDH1 ,Paraganglioma ,medicine ,PTEN ,Humans ,Genes, Tumor Suppressor ,Promoter Regions, Genetic ,Aged ,biology ,CpG Island Methylator Phenotype ,Promoter ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Phenotype ,Long Interspersed Nucleotide Elements ,Oncology ,Abdominal Neoplasms ,DNA methylation ,biology.protein ,Cancer research ,CpG Islands ,Female - Abstract
Purpose: This study aims to quantitatively assess promoter and global methylation changes in pheochromocytomas and abdominal paragangliomas and its relation to tumor phenotypes.Experimental Design: A panel of 53 primary tumors (42 benign, 11 malignant) was analyzed by quantitative bisulfite pyrosequencing. Based on methylation levels in the tumor suppressor genes, p16INK4A, CDH1, DCR2, RARB, RASSF1A, NORE1A, TP73, APC, DAPK1, p14ARF, and PTEN, a CpG island methylator phenotype (CIMP) was defined as concerted hypermethylation in three or more genes. Mean Z scores for the hypermethylated promoters were calculated to characterize overall promoter methylation. Global DNA methylation was quantified for LINE-1 promoter sequences and by using luminescent methylation analysis.Results: Five primary tumors (9.4%) exhibited a CIMP phenotype, four of which were malignant paragangliomas. CIMP was significantly associated with malignant behavior (P = 0.005) and younger age at presentation (P < 0.007) but did not result from BRAF V600E mutation. Global hypomethylation of LINE-1 elements was observed in tumors compared with normal adrenal samples (P < 0.02).Conclusion: We here describe the identification of CIMP in abdominal paragangliomas and a strong association of this phenotype with malignant behavior, as well as young age at presentation. The findings raise a prospective for potential benefits of epigenetically acting drugs for a subgroup of young abdominal paraganglioma patients with adverse prognosis.
- Published
- 2008
43. Nuclear DNA content and survival in medullary thyroid carcinoma
- Author
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Hans-Olov Adami, Lars Grimelius, Martin Bäckdahl, Eva Tallroth Ekman, Reinhold Bergström, Gert Auer, and Ulla Bergholm
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Percentile ,Pathology ,Medullary cavity ,Aneuploidy ,Biology ,medicine.disease ,Confidence interval ,Nuclear DNA ,Thyroid carcinoma ,chemistry.chemical_compound ,DNA profiling ,chemistry ,Internal medicine ,medicine ,DNA - Abstract
In a nationwide study of medullary thyroid carcinoma, the relation between nuclear DNA content and survival was studied in 211 patients with complete follow-up of up to 27 years. Morphologically identified tumor cells were analyzed by an image cytometric method. The DNA histograms were classified (1) by an objective method in which the degree of aneuploidy was defined as the percentage number of tumor cells with DNA values exceeding the 90th percentile of diploid control cells (P90), and (2) according to a subjective evaluation of whether the DNA profiles represented a euploid or an aneuploid DNA pattern. Both classifications separated groups with marked differences (P less than 0.001) in survival. A multivariate proportional hazards analysis indicated that each method provided additional information when the other one was taken into account. In patients whose tumors were classified according to the objective P90 method 1, the relative hazards (with 95% confidence interval) in the groups with P90 values of 36% to 69% and greater than or equal to 70% were 1.6 (0.9-2.8) and 2.1 (1.1-4.0) respectively, compared with the reference group. With the subjective method 2 the corresponding figure for the group with aneuploid tumors was 1.7 (1.0-2.0) compared with the group with euploid tumors.
- Published
- 1990
44. Detailed assessment of chromosome 22 aberrations in sporadic pheochromocytoma using array-CGH
- Author
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Patrick G. Buckley, Kiran Kumar Mantripragada, Simon G. Gregory, Catharina Larsson, Caroline Jarbo, Martin Bäckdahl, Teresita Díaz de Ståhl, Henning Dralle, Göran Åkerström, Jan P. Dumanski, Magdalena Benetkiewicz, Arkadiusz Piotrowski, Janos Geli, Oliver Gimm, Gunnar Westin, and Cordelia Langford
- Subjects
Adult ,Male ,endocrine system ,Cancer Research ,Pathology ,medicine.medical_specialty ,Monosomy ,endocrine system diseases ,Chromosomes, Human, Pair 22 ,Aneuploidy ,Pheochromocytoma ,Biology ,Tumor heterogeneity ,medicine ,Humans ,neoplasms ,Aged ,Chromosome Aberrations ,Low resolution ,Cytogenetics ,Nucleic Acid Hybridization ,Genomics ,Middle Aged ,medicine.disease ,Molecular biology ,stomatognathic diseases ,medicine.anatomical_structure ,Oncology ,Chromosomes, Human, Pair 1 ,Female ,Chromosome Deletion ,Adrenal medulla ,Chromosome 22 - Abstract
Pheochromocytoma is a predominantly sporadic neuroendocrine tumor derived from the adrenal medulla. Previous low resolution LOH and metaphase-CGH studies reported the loss of chromosomes 1p, 3q, 17p and 22q at various frequencies. However, the molecular mechanism(s) behind development of sporadic pheochromocytoma remains largely unknown. We have applied high-resolution tiling-path microarray-CGH with the primary aim to characterize copy number imbalances affecting chromosome 22 in 66 sporadic pheochromocytomas. We detected copy number alterations on 22q at a frequency of 44%. The predominant finding was monosomy 22 (30%), followed by terminal deletions in 8 samples (12%) and a single interstitial deletion. We further applied a chromosome 1 tiling-path array in 7 tumors with terminal deletions of 22q and found deletions of 1p in all cases. Our overall results suggest that at least 2 distinct regions on both 22q and 1p are important in the tumorigenesis of sporadic pheochromocytoma. A large proportion of pheochromocytomas also displayed indications of cellular heterogeneity. Our study is to our knowledge the first array-CGH study of sporadic pheochromocytoma. Future analysis of this tumor type should preferably be performed in the context of the entire human genome using genome-wide array-CGH, which is a superior methodological approach. Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.
- Published
- 2005
45. Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytomas and abdominal paragangliomas
- Author
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Catharina Larsson, Tony Frisk, Tobias Carling, Martin Bäckdahl, Brita Nord, Janos Geli, Tomas J. Ekström, and Elisabeth Elder
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Tumor suppressor gene ,Adrenal Gland Neoplasms ,Loss of Heterozygosity ,Pheochromocytoma ,Biology ,Retinoblastoma Protein ,Paraganglioma ,Loss of heterozygosity ,medicine ,Humans ,Gene silencing ,RNA, Messenger ,Oncogene ,Gene Expression Profiling ,Nuclear Proteins ,Histone-Lysine N-Methyltransferase ,Methylation ,DNA Methylation ,medicine.disease ,DNA-Binding Proteins ,Real-time polymerase chain reaction ,Oncology ,Chromosomes, Human, Pair 1 ,Abdominal Neoplasms ,Case-Control Studies ,Female ,Gene Deletion ,Transcription Factors - Abstract
Pheochromocytomas and abdominal paragangliomas are rare catecholamine-producing tumours arising from neural crest-derived chromaffin cells. Frequent deletions of several distinct regions on the short arm of chromosome 1 suggest their involvement in the tumourigenesis process. The RIZ1 tumour suppressor encoded by the RIZ gene in 1p36.21 represents an attractive candidate target for the distal 1p deletions in these tumours. A panel of 18 pheochromocytomas (14 benign, and 4 malignant) and 11 abdominal paragangliomas (4 benign, and 7 malignant) were characterised for somatic deletions and mRNA expression status of RIZ1 using loss of heterozygosity (LOH) analysis and real-time quantitative PCR, respectively. Furthermore, we evaluated the methylation status of the RIZ1 promoter utilising methylation-specific PCR (MSP). Intragenic LOH at the RIZ locus was detected in 10 of 16 informative cases (62%), including 8 of 12 pheochromocytomas (67%) and 2 of 4 paragangliomas (50%). RIZ1 mRNA appeared to be significantly under-expressed in the tumour samples compared to normal adrenal controls (mean 0.6 vs. 1.0, p
- Published
- 2005
46. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas
- Author
-
B. Hallengren, Göran Wallin, U. Bergholm, Catharina Larsson, Judith V.M.G. Bovée, Jan Zedenius, Ann Svensson, Günther Weber, Martin Bäckdahl, and Lars Grimelius
- Subjects
Threonine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Molecular Sequence Data ,Clinical Biochemistry ,Multiple Endocrine Neoplasia Type 2a ,RET proto-oncogene ,Gene mutation ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Proto-Oncogene Mas ,Biochemistry ,Exon ,Methionine ,Endocrinology ,Germline mutation ,Proto-Oncogene Proteins ,Internal medicine ,Proto-Oncogenes ,medicine ,Drosophila Proteins ,Humans ,Point Mutation ,Thyroid Neoplasms ,Codon ,DNA Primers ,Mutation ,Base Sequence ,Point mutation ,Multiple Endocrine Neoplasia ,Proto-Oncogene Proteins c-ret ,Biochemistry (medical) ,Receptor Protein-Tyrosine Kinases ,Prognosis ,medicine.disease ,Medullary carcinoma ,Carcinoma, Medullary - Abstract
The hereditary multiple endocrine neoplasia syndromes types 2A and B (MEN 2A and B) were recently linked to germline mutations in the RET proto-oncogene, altering one of five cysteine residues in exon 10 or 11 (MEN 2A), or substituting a methionine for a threonine at codon 918 in exon 16 (MEN 2B). The latter mutation also occurs somatically in some sporadic medullary thyroid carcinomas (MTC), and has in a previous study been correlated with a less favorable clinical outcome. In the present study, 46 MTCs were selected for investigation of the codon 918 mutation. The mutation was found in 29 tumors (63%), and was significantly correlated with a poor outcome, with regard to distant metastasis or tumor recurrence (p < 10(-4)). Two tumors showed multifocal growth and C-cell hyperplasia, and these patients were therefore also investigated for germline mutations in exons 10, 11 and 16. The codon 918 mutation was found only in the tumors, thus of somatic origin. The RET codon 918 mutation may have prognostic impact, and therefore preoperative assessment may influence decision-making in the treatment of patients suffering from MTC.
- Published
- 1995
47. KI-67 AND hTERT expression can aid in the distinction between malignant and benign pheochromocytoma and paraganglioma
- Author
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A Gruber, Catharina Larsson, M Hou, P Pisa, Anders Höög, Elisabeth Elder, Martin Bäckdahl, U Enberg, and Dawei Xu
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Telomerase ,Adolescent ,Adrenal Gland Neoplasms ,Gene Expression ,Pheochromocytoma ,Biology ,Pathology and Forensic Medicine ,Metastasis ,Surgical pathology ,Diagnosis, Differential ,Paraganglioma ,Antigens, CD ,Antigens, Neoplasm ,Predictive Value of Tests ,medicine ,Biomarkers, Tumor ,Humans ,Telomerase reverse transcriptase ,Neoplasm Invasiveness ,RNA, Messenger ,neoplasms ,In Situ Hybridization ,Aged ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,Middle Aged ,medicine.disease ,Prognosis ,Immunohistochemistry ,DNA-Binding Proteins ,Ki-67 Antigen ,Cytopathology ,Ki-67 ,Abdominal Neoplasms ,biology.protein ,Basigin ,Matrix Metalloproteinase 2 ,Female - Abstract
The clinical and histopathological distinction between benign and malignant pheochromocytomas and paragangliomas is difficult, and reliable diagnostic markers are lacking. Here we have evaluated the prognostic value of human telomerase reverse transcriptase (hTERT) gene expression detected by reverse transcription PCR (RT-PCR); telomerase activity (TA) measured by TRAP (telomeric repeat amplification protocol) assay; immunohistochemical staining for Ki-67/MIB-1; and the mRNA expression of matrix metalloproteinase (MMP)–2 and EMMPRIN (extracellular matrix metalloproteinase inducer) analyzed by in situ hybridization in 32 primary pheochromocytomas or abdominal paragangliomas. hTERT was expressed in 7/11 malignant tumors (defined as presence of metastasis and/or extensive local invasion) as compared with in 2/21 benign tumors. All of the benign tumors showed
- Published
- 2003
48. Loss of heterozygosity on the short arm of chromosome 1 in pheochromocytoma and abdominal paraganglioma
- Author
-
Martin Bäckdahl, Tobias Carling, Brita Nord, Catharina Larsson, Claes Juhlin, Anders Höög, and Elisabeth Elder
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adrenal Gland Neoplasms ,Loss of Heterozygosity ,Pheochromocytoma ,Loss of heterozygosity ,Paraganglioma ,Internal medicine ,medicine ,Humans ,Genes, Tumor Suppressor ,Aged ,Gynecology ,Paraganglioma, Extra-Adrenal ,business.industry ,Chromosome ,Middle Aged ,medicine.disease ,Endocrinology ,Cardiothoracic surgery ,Chromosomes, Human, Pair 1 ,Surgery ,Female ,business - Abstract
Les pheochromocytomes et les paraganglions abdominaux, dont l'origine est un paraganglion sympathique, sont des tumeurs produisant des catecholamines, situees, respectivement, a l'interieur ou a l'exterieur de la medullosurrenale. On a suggere que l'amputation du bras court du chromosome 1 pourrait etre un des evenements genetiques importants dans leur tumorogenese et pourrait expliquer une etiologie genetique commune. Le but de cette etude a ete de definir les regions chromosomiques sur 1p qui pourraient etre impliquees dans le developpement de ces types de tumeur. A la recherche de la perte d'heterozygosite (PH) sur 1p par le phenotype de 15 marqueurs microsatellites repandus sur le bras du chromosome, nous avons analyse 46 cas de pheochromocytomes (31 benignes, 6 malignes, 9 hereditaires) et sept paragangliomes (3 benignes, 4 malignes) provenant de 50 patients. Globalement, la PH a ete detectee dans 33/46 pheochromocytomes (72%) et dans 6/7 (86%) paragangliomes. Trois zones minimes d'amputation chevauchante ont ete identifiees, une telomerique de D1S1612 (1p36.2-pter), une centromerique de D1S429 (1cen-p13) et une dans l'intervalle 18 cM defini par D1S2134 et D1S1669 (1p32). Cette derniere region contient le gene LAR («leukocyte common-antigen-related) qui montre une expression alteree en cas de pheochromocytome sporadique du rat. En conclusion, le chromosome 1p pourrait etre le site d'au moins trois localisations de suppresion tumorale impliquees dans la tumorogenese des pheochromocytomes et des paragangliomes abdominaux. D'autres etudes de ces regions et du gene «LAR» seraient utiles.
- Published
- 2002
49. Genetic background of adrenocortical tumor development
- Author
-
Martin Bäckdahl, Catharina Larsson, and Magnus Kjellman
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,business.industry ,Adrenal cortex ,Adrenalectomy ,medicine.medical_treatment ,Adrenocortical Tumor ,medicine.disease ,Genetic determinism ,Adrenal Cortex Neoplasms ,medicine.anatomical_structure ,Adrenal Cortex ,Medicine ,Humans ,Surgery ,Congenital adrenal hyperplasia ,Familial Cancer ,business ,Multiple endocrine neoplasia ,Carney complex - Abstract
The increasing occurrence of incidentally discovered benign adrenocortical tumors has become a clinical dilemma because of the difficulties in differentiating them from their malignant counterpart. Adrenocortical tumors are associated with familial cancer syndromes such as the Beckwith-Wiedemann syndrome, the Li-Fraumeni syndrome, the Carney complex, multiple endocrine neoplasia type 1, congenital adrenal hyperplasia, and the McCune-Albright syndrome. Genetic events are known to take place on the chromosomal and gene level in sporadic adrenocortical tumors.
- Published
- 2001
50. Expression of matrix metalloproteinase gelatinase A messenger ribonucleic acid in parathyroid carcinomas
- Author
-
Lars-Ove Farnebo, Catharina Larsson, Ann Svensson, Martin Bäckdahl, Kerstin Sandelin, Lars Grimelius, Filip Farnebo, and Norman W. Thompson
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,DNA, Complementary ,Gelatinase A ,Gene Expression Regulation, Enzymologic ,Metastasis ,medicine ,Gelatinase ,Humans ,RNA, Messenger ,In Situ Hybridization ,Aged ,Aged, 80 and over ,Hyperparathyroidism ,business.industry ,Carcinoma ,Proteolytic enzymes ,Cancer ,Fibroblasts ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Parathyroid Neoplasms ,Parathyroid carcinoma ,Matrix Metalloproteinase 2 ,Surgery ,business ,Primary hyperparathyroidism - Abstract
Background: The incidence of parathyroid cancer in patients with hyperparathyroidism is less than 1%. However, these few cases cause diagnostic problems in the absence of clear-cut invasion of adjacent organs or metastasis. New markers are needed to increase diagnostic accuracy. Methods: Thirty-one parathyroid tumors from patients with primary hyperparathyroidism were collected worldwide. Eighteen tumors were classified as unequivocal cancers, whereas 13 tumors were considered equivocal because of a lack of infiltrative growth or evidence of recurrence. Paraffin sections were hybridized with a 35S-labeled riboprobe complementary to gelatinase A mRNA, dipped in photographic emulsion, developed, counterstained, and then evaluated by light- and dark-field microscopy. Results: Fourteen of the 18 unequivocal parathyroid cancers expressed gelatinase A, as compared with the equivocal tumors, of which only 4 of 13 showed expression. The strongest hybridization signal was seen in stromal cells at the tumor border, most likely fibroblasts and macrophages. No expression was detected in tumor cells. Conclusions: Invasive growth of many tumors is facilitated by proteolytic enzymes, such as gelatinase A. The presence of gelatinase A mRNA in parathyroid tumors strengthens the suspicion of malignancy but cannot be used as a definitive marker of malignancy. (Surgery 1999;126:1183-7.)
- Published
- 1999
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