| 1. |
- Bausch, Birke, et al.
(författare)
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Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention
- 2017
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Ingår i: JAMA Oncology. - : AMER MEDICAL ASSOC. - 2374-2437 .- 2374-2445. ; 3:9, s. 1204-1212
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.
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| 2. |
- Björkman, Frida, et al.
(författare)
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Sex and maturity status affected the validity of a submaximal cycle test in adolescents.
- 2018
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 107:1, s. 126-133
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Tidskriftsartikel (refereegranskat)abstract
- AIM: This study assessed the validity and reliability of the Ekblom-Bak (EB) submaximal cycle test in adolescents and identified any sex- or maturity-related factors for prediction errors.METHODS: We recruited 50 healthy subjects through a public announcement in Stockholm, Sweden, in 2016. The 27 boys and 23 girls were aged 10-15 years and in Tanner stages I-IV. They performed an EB test and incremental treadmill running test for direct measurement of maximal oxygen uptake (VO2 max).RESULTS: The estimation error of VO2 max was 0.09 L/min. The correlation (r) was 0.86, and the standard error of the estimate (SEE) was 0.29 L/min. The largest overestimation was seen in prepubertal boys (0.49 L/min). The best precision of the EB test was achieved when boys in Tanner stages I and II were re-calculated using the prediction equation developed for adult women. This yielded a mean difference of -0.05 L/min, r = 0.92 and SEE 0.23 L/min, in the entire sample. The prediction error was lowered in boys, but not girls, with increasing pubertal maturity.CONCLUSION: The EB test was reasonably valid in adolescents, seemed to be related to sex and maturity status, and our findings support its use.
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| 3. |
- Christofer Juhlin, C., et al.
(författare)
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Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
- 2015
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:9, s. 542-554
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Tidskriftsartikel (refereegranskat)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.
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| 4. |
- Paulsson, Johan O., et al.
(författare)
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Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 250:2, s. 183-194
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Tidskriftsartikel (refereegranskat)abstract
- 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 CALR, RB1, and MSH2, and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT, 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.
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| 5. |
- Stenman, Adam
(författare)
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Genetic and molecular background of pheochromocytoma and paraganglioma
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pheochromocytomas (PCC) and abdominal paragangliomas (PGL), collectively denoted PPGL, are neuroendocrine tumors (NET) with a highly diverse genetic and molecular etiology, arisen in the adrenal medulla and abdominal paraganglia respectively. The tumors often cause cardiovascular symptoms due to the high production of catecholamines, and malignancy occurs in 10% of the PCCs and 30% of the PGLs. The genetic background of the PPGL disease constitutes of hereditary mutations in a growing list of susceptibility genes, although a large subset of the sporadic tumors still has an unknown etiology. This thesis work aimed to further characterize the genetic and molecular background of PPGL, in order to contribute to better diagnosis, prognosis and treatment for the patients. In the first study we investigated the role of susceptibility gene promoter methylation in PPGL. By studying the gene expression and assessing the promoter methylation levels, it was found that the VHL gene is epigenetically inactivated in PPGL. Subsequently, in order to investigate the established susceptibility genes in a large cohort, we used a targeted sequencing approach in the second study and found that next-generation sequencing is fast and cost-effective method for mutational screening of PPGL. Additionally, the NF1 gene was found to be the most frequently mutated gene, and in the third study we used the NF1 mutational status obtained in the second study to investigate if immunohistochemistry could be used as a screening tool for NF1 mutations. We found a strong sensitivity but poor specificity for the method and therefore recommend genetic screening as the most efficient tool to identify NF1 patients. The list of PPGL susceptibility genes is constantly growing, and one of the latest genes verified is the HRAS gene. In the fourth study we screened a large cohort of PPGL for mutations in the HRAS gene and compared with the overall gene expression obtained using a mRNA microarray approach. Taken together with HRAS mutations in the literature, the overall HRAS mutation frequency was calculated to 5.2% in PPGL. The gene expression profiling showed that the HRAS mutated tumors clustered together with the NF1- and RET-mutated tumors that are associated with activation of kinase pathways. With the mutational information obtained in the second study, we were able to screen PCCs without known genetic drivers. In the fifth study, these tumors underwent whole-exome sequencing, detecting recurrent mutations in the KMT2D gene. After screening of a verification cohort, a total KMT2D mutation frequency of 14% was established. In the sixth study we screened PGLs for mutations in the KMT2D gene. All PGLs exhibited wild-type however KMT2D gene over-expression was observed in PGLs compared to normal adrenal samples. These results would imply dysregulation of methyltransferase as a novel disease mechanism in PPGL. In summary, the studies included in the thesis have increased the knowledge of the genetic and molecular background of PPGL. The results may therefore in the long run contribute to better diagnosis, prognosis and development of future treatment options for the patients.
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| 6. |
- Stenman, Adam, et al.
(författare)
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HRAS mutation prevalence and associated expression patterns in pheochromocytoma
- 2016
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Ingår i: Genes, Chromosomes and Cancer. - : WILEY-BLACKWELL. - 1045-2257 .- 1098-2264. ; 55:5, s. 452-459
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
- Stenman, Adam, et al.
(författare)
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Immunohistochemical NF1 Analysis Does not Predict NF1 Gene Mutation Status in Pheochromocytoma.
- 2015
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Ingår i: Endocrine pathology. - : Springer. - 1046-3976 .- 1559-0097. ; 26:1, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas (PCCs) are tumors originating from the adrenal medulla displaying a diverse genetic background. While most PCCs are sporadic, about 40 % of the tumors have been associated with constitutional mutations in one of at least 14 known susceptibility genes. As 25 % of sporadic PCCs harbor somatic neurofibromin 1 gene (NF1) mutations, NF1 has been established as the most recurrently mutated gene in PCCs. To be able to pinpoint NF1-related pheochromocytoma (PCC) disease in clinical practice could facilitate the detection of familial cases, but the large size of the NF1 gene makes standard DNA sequencing methods cumbersome. The aim of this study was to examine whether mutations in the NF1 gene could be predicted by immunohistochemistry as a method to identify cases for further genetic characterization. Sixty-seven PCCs obtained from 67 unselected patients for which the somatic and constitutional mutational status of NF1 was known (49 NF1 wild type, 18 NF1 mutated) were investigated for NF1 protein immunoreactivity, and the results were correlated to clinical and genetic data. NF1 immunoreactivity was absent in the majority of the PCCs (44/67; 66 %), including 13 out of 18 cases (72 %) with a somatic or constitutional NF1 mutation. However, only a minority of the NF1 wild-type PCCs (18/49; 37 %) displayed retained NF1 immunoreactivity, thereby diminishing the specificity of the method. We conclude that NF1 immunohistochemistry alone is not a sufficient method to distinguish between NF1-mutated and non-mutated PCCs. In the clinical context, genetic screening therefore remains the most reliable tool to detect NF1-mutated PCCs.
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| 8. |
- Stenman, Adam, et al.
(författare)
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Molecular Profiling of Pheochromocytoma and Abdominal Paraganglioma Stratified by the PASS Algorithm Reveals Chromogranin B as Associated With Histologic Prediction of Malignant Behavior
- 2019
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Ingår i: American Journal of Surgical Pathology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0147-5185 .- 1532-0979. ; 43:3, s. 409-421
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGL, are believed to exhibit malignant potential-but only subsets of cases will display full-blown malignant properties. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) algorithm is a proposed histologic system to detect potential for aggressive behavior, but little is known regarding the coupling to underlying molecular genetics. In this study, a total of 92 PPGLs, previously characterized for susceptibility gene status and mRNA expressional profiles, were histologically assessed using the PASS criteria. A total of 32/92 PPGLs (35%) exhibited a PASS score amp;gt;= 4, including all 8 cases with malignant behavior (7 with known metastases and 1 with extensively infiltrative local recurrence). Statistical analyzes between expressional data and clinical parameters as well as individual PASS criteria yielded significant associations to Chromogranin B (CHGB), BRCA2, HIST1H3B, BUB1B, and RET to name a few, and CHGB had the strongest correlation to both PASS and metastasis/local recurrence of all analyzed genes. Evident CHGB downregulation was observed in PPGLs with high PASS and overtly malignant behavior, and was also associated with shorter disease-related survival. This finding was validated using quantitative real-time polymerase chain reaction, in which CHGB expression correlated with both PASS and metastasis/local recurrence with consistent findings obtained in the TCGA cohort. Moreover, immunohistochemical analyses of subsets of tumors showed a correlation between high PASS scores and negative or weak CHGB protein expression. Patients with PPGLs obtaining high PASS scores postoperatively, also exhibited low preoperative plasma levels of CHGB. These data collectively point out CHGB as a possible preoperative and postoperative marker for PPGLs with potential for aggressive behavior.
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| 9. |
- Stenman, Adam, et al.
(författare)
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Pan-genomic characterization of high-risk pediatric papillary thyroid carcinoma
- 2021
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 28:5, s. 337-351
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric papillary thyroid carcinomas (pPTCs) are often indolent tumors with excellent long- term outcome, although subsets of cases are clinically troublesome and recur. Although it is generally thought to exhibit similar molecular aberrancies as their counterpart tumors in adults, the pan-genomic landscape of clinically aggressive pPTCs has not been previously described. In this study, five pairs of primary and synchronously metastatic pPTC from patients with high-risk phenotypes were characterized using parallel whole-genome and -transcriptome sequencing. Primary tumors and their metastatic components displayed an exceedingly low number of coding somatic mutations and gross chromosomal alterations overall, with surprisingly few shared mutational events. Two cases exhibited one established gene fusion event each (SQSTM1-NTRK3 and NCOA4-RET) in both primary and metastatic tissues, and one case each was positive for a BRAF V600E mutation and a germline truncating CHEK2 mutation, respectively. One single case was without apparent driver events and was considered as a genetic orphan. Non-coding mutations in cancer-associated regions were generally not present. By expressional analyses, fusion-driven primary and metastatic pPTC clustered separately from the mutation-driven cases and the sole genetic orphan. We conclude that pPTCs are genetically indolent tumors with exceedingly stable genomes. Several mutations found exclusively in the metastatic samples which may represent novel genetic events that drive the metastatic behavior, and the differences in mutational compositions suggest early clonal divergence between primary tumors and metastases. Moreover, an overrepresentation of mutational and expressional dysregulation of immune regulatory pathways was noted among fusion-positive pPTC metastases, suggesting that these tumors might facilitate spread through immune evasive mechanisms.
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| 10. |
- Stenman, Adam, et al.
(författare)
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Pan-genomic sequencing reveals actionable cdkn2a/2b deletions and kataegis in anaplastic thyroid carcinoma
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:24
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic thyroid carcinoma (ATC) is a lethal malignancy characterized by poor response to conventional therapies. Whole-genome sequencing (WGS) analyses of this tumor type are limited, and we therefore interrogated eight ATCs using WGS and RNA sequencing. Five out of eight cases (63%) displayed cyclin-dependent kinase inhibitor 2A (CDKN2A) abnormalities, either copy number loss (n = 4) or truncating mutations (n = 1). All four cases with loss of the CDKN2A locus (encoding p16 and p14arf) also exhibited loss of the neighboring CDKN2B gene (encoding p15ink4b), and displayed reduced CDKN2A/2B mRNA levels. Mutations in established ATC-related genes were observed, including TP53, BRAF, ARID1A, and RB1, and overrepresentation of mutations were also noted in 13 additional cancer genes. One of the more predominant mutational signatures was intimately coupled to the activity of Apolipoprotein B mRNA-editing enzyme, the catalytic polypeptide-like (APOBEC) family of cytidine deaminases implied in kataegis, a focal hypermutation phenotype, which was observed in 4/8 (50%) cases. We corroborate the roles of CDKN2A/2B in ATC development and identify kataegis as a recurrent phenomenon. Our findings pinpoint clinically relevant alterations, which may indicate response to CDK inhibitors, and focal hypermutational phenotypes that may be coupled to improved responses using immune checkpoint inhibitors.
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