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Backman, Samuel
Publications (10 of 12) Show all publications
Backman, S., Åkerström, T., Maharjan, R., Cupisti, K., Willenberg, H. S., Hellman, P. & Björklund, P. (2019). RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas. Scientific Reports, 9, Article ID 6269.
Open this publication in new window or tab >>RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6269Article in journal (Refereed) Published
Abstract [en]

Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-383193 (URN)10.1038/s41598-019-41525-2 (DOI)000465001600023 ()31000732 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-07-24 Created: 2019-07-24 Last updated: 2019-07-24Bibliographically approved
Backman, S., Bajic, D., Crona, J., Hellman, P., Skogseid, B. & Stålberg, P. (2019). Whole genome sequencing of apparently mutation-negative MEN1 patients. European Journal of Endocrinology, 182(1), 35-45
Open this publication in new window or tab >>Whole genome sequencing of apparently mutation-negative MEN1 patients
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2019 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, no 1, p. 35-45Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-401244 (URN)10.1530/eje-19-0522 (DOI)
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-10Bibliographically approved
Paulsson, J., Backman, S., Wang, N., Stenman, A., Crona, J., Thutkawkorapin, J., . . . Juhlin, C. (2019). Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation. The Journal of Pathology
Open this publication in new window or tab >>Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
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2019 (English)In: The Journal of Pathology, ISSN 1096-9896Article in journal (Refereed) Epub ahead of print
Abstract [en]

The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan‐genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole‐genome sequencing (WGS). The FTC displayed mutations in CALRRB1, and MSH2, and the PDTC exhibited mutations in TP53DROSHAAPCTERT, and additional DNA repair genes – associated with an immense increase in sub‐clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53‐associated regulation of DNA repair and identified important sub‐clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-401241 (URN)10.1002/path.5359 (DOI)
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-08Bibliographically approved
Maharjan, R., Backman, S., Åkerström, T., Hellman, P. & Björklund, P. (2018). Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival. Scientific Reports, 8, Article ID 8610.
Open this publication in new window or tab >>Comprehensive analysis of CTNNB1 in adrenocortical carcinomas: Identification of novel mutations and correlation to survival
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8610Article in journal (Refereed) Published
Abstract [en]

The Wnt/β-Catenin signaling pathway is one of the most frequently altered pathways in adrenocortical carcinomas (ACCs). The aim of this study was to investigate the status of Wnt/β-Catenin signaling pathway by analyzing the expression level of β-Catenin and the mutational status of APC, AXIN2, CTNNB1, and ZNRF3 in ACCs. Mutations in APC, CTNNB1, ZNRF3 and homozygous deletions in ZNRF3 were observed in 3.8% (2/52), 11.5% (6/52), 1.9% (1/52) and 17.3% (9/52) of the cohort respectively. Novel interstitial deletions in CTNNB1 spanning intron 1 to exon 3/intron 3 were also found in 7.7% (4/52) of the tumours. All the observed alterations were mutually exclusive. Nuclear accumulation of β-Catenin, increased expression of Cyclin D1 and significantly higher expression of AXIN2 (p = 0.0039), ZNRF3 (p = 0.0032) and LEF1(p = 0.0090) observed in the tumours harbouring the deletion in comparison to tumours without CTNNB1 mutation demonstrates that the truncated β-Catenin is functionally active and erroneously activates the downstream targets. Significantly lower overall survival rate in patients with tumours harbouring alterations in APC/CTNNB1/ZNRF3 in comparison to those without mutation was observed. In conclusion, the discovery of novel large deletions in addition to the point mutations in CTNNB1 infers that activation of Wnt/β-Catenin pathway via alterations in CTNNB1 occurs frequently in ACCs. We also confirm that alterations in Wnt/β-Catenin signaling pathway members have a negative effect on overall survival of patients.

Keywords
adrenocortical carcinomas, CTNNB1, mutation, β-Catenin, survival
National Category
Cell and Molecular Biology Cancer and Oncology Medical and Health Sciences
Research subject
Molecular Genetics; Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-325980 (URN)10.1038/s41598-018-26799-2 (DOI)000434122600035 ()29872083 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2018-11-12Bibliographically approved
Björklund, P. & Backman, S. (2018). Epigenetics of pheochromocytoma and paraganglioma. Molecular and Cellular Endocrinology, 469, 92-97
Open this publication in new window or tab >>Epigenetics of pheochromocytoma and paraganglioma
2018 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 469, p. 92-97Article in journal (Refereed) Published
Abstract [en]

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising in the medullae of the adrenal glands or in paraganglia. The knowledge of the tumor biology of these lesions has increased dramatically during the past two decades and more than a dozen recurrently mutated genes have been identified. Different clusters have been described that share epigenetic signatures. Mutations in the succinate dehydrogenase complex subunit genes play a pivotal role in reprogramming the epigenetic state of these tumors by inhibiting epigenetic regulators such as TET enzymes and histone demethylases. Another subgroup of tumors carries hypomethylated genomes, and overexpression of several microRNAs has been described. While much remains to be investigated regarding the epigenetics of PPGLs, it is clear that it plays an important role in PPGL biology.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2018
Keywords
Pheochromocytoma, Paraganglioma, Epigenetics, Adrenal, Methylation
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-369529 (URN)10.1016/j.mce.2017.06.016 (DOI)000447949400012 ()28630023 (PubMedID)
Funder
Swedish Cancer Society, 15 0130Erik, Karin och Gösta Selanders Foundation
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved
Crona, J., Backman, S., Welin, S., Taieb, D., Hellman, P., Stålberg, P., . . . Pacak, K. (2018). RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective. Cancers, 10(12), Article ID 518.
Open this publication in new window or tab >>RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective
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2018 (English)In: Cancers, ISSN 2072-6694, Vol. 10, no 12, article id 518Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

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

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

Keywords
MTOR, PNET, biomarker, next-generation sequencing
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-320669 (URN)10.21873/anticanres.11367 (DOI)000396901200038 ()28179320 (PubMedID)
Available from: 2017-04-23 Created: 2017-04-23 Last updated: 2019-10-30Bibliographically approved
Backman, S., Maharjan, R., Falk Delgado, A., Crona, J., Cupisti, K., Stålberg, P., . . . Björklund, P. (2017). Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations. Scientific Reports, 7, Article ID 44943.
Open this publication in new window or tab >>Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 44943Article in journal (Refereed) Published
Abstract [en]

Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.

National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-320646 (URN)10.1038/srep44943 (DOI)000397026500001 ()28327598 (PubMedID)
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2019-10-30Bibliographically approved
Crona, J., Backman, S., Kugelberg, J., Maharjan, R., Björklund, P. & Hellman, P. (2016). Multiregion Analysis Reveal Evolutionary Patterns and a Chromosomal Instability Signature in Pancreatic Neuroendocrine Tumours. In: : . Paper presented at 13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 09-11, 2016, Barcelona, SPAIN (pp. 6-6). , 103
Open this publication in new window or tab >>Multiregion Analysis Reveal Evolutionary Patterns and a Chromosomal Instability Signature in Pancreatic Neuroendocrine Tumours
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2016 (English)Conference paper, Published paper (Refereed)
Keywords
Cancer evolution, Molecular genetics, Neuroendocrine tumor
National Category
Cancer and Oncology Endocrinology and Diabetes Neurology
Identifiers
urn:nbn:se:uu:diva-313700 (URN)000386481600015 ()
Conference
13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 09-11, 2016, Barcelona, SPAIN
Available from: 2017-01-23 Created: 2017-01-23 Last updated: 2019-10-30
Åkerström, T., Willenberg, H. S., Cupisti, K., Ip, J., Backman, S., Moser, A., . . . Hellman, P. (2015). Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.. Endocrine-Related Cancer, 22(5), 735-744
Open this publication in new window or tab >>Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.
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2015 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 5, p. 735-744Article in journal (Refereed) Published
Abstract [en]

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 Ca(2) (+) 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 Ca(2) (+) levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

Keywords
ATP1A1; CACNA1D; KCNJ5; primary aldosteronism; aldosterone-producing adenoma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-266639 (URN)10.1530/ERC-15-0321 (DOI)000364022400010 ()26285814 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2015-11-10 Created: 2015-11-10 Last updated: 2017-12-01
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