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Somatic Mutations in H-RAS in Sporadic Pheochromocytoma and Paraganglioma Identified by Exome Sequencing
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
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2013 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 7, E1266-E1271 p.Article in journal (Refereed) Published
Abstract [en]

Context: Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL. Objectives: The aim of this study was to identify novel disease causing genes in PCC and PGL tumors. Design, setting, and participants: Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions. Results: Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H-RAS tumors were exclusively found in male patients (P = .007). Conclusions: We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target.

Place, publisher, year, edition, pages
2013. Vol. 98, no 7, E1266-E1271 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-208673DOI: 10.1210/jc.2012-4257ISI: 000322780600017OAI: oai:DiVA.org:uu-208673DiVA: diva2:653912
Available from: 2013-10-07 Created: 2013-10-07 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Charting the Genetic Landscape and Clonal Architectures of Pheochromocytoma
Open this publication in new window or tab >>Charting the Genetic Landscape and Clonal Architectures of Pheochromocytoma
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genotypic and phenotypic inter patient heterogeneity characterize pheochromocytoma and paraganglioma (PPGL). Up to 60% of PPGL are associated with either somatic or germline mutations in at least 14 established disease causing genes. Consequently, a comprehensive screening test for PPGL patients utilizing standard techniques is not feasible and in the diagnostic approach, multiple different phenotype guided gene prioritization protocols have been utilized. This may result in misdiagnosis, especially in patients with sporadic presentation. Diagnostic testing of somatic mutations in tumour material is not performed due to the lack of actionable results.

The aims of this study were, (1) to investigate the use of novel sequencing techniques in a clinical application, (2) to discover novel PPGL disease causing loci using novel sequencing techniques, (3) to characterize a large cohort of PPGL for mutations in known disease causing genes and to analyse corresponding genotype-phenotype correlations, (4) to dissect the molecular and genetic landscape of MEN2 PPGL and (5) to determine the clonal architecture and heterogeneity within, and in-between matched PPGL.

For these purposes we studied PPGL tumours from a total of 96 patients using targeted and/or whole exome enrichment, capillary and high throughput sequencing as well as genome wide array based genotyping. Novel bioinformatics pipelines were constructed for raw data processing and downstream interpretation. Quantitative PCR, western blot and immunohistochemistry were utilized in order to characterize molecular traits. Selected experimental findings were correlated to patient phenotype.

We conclude that novel sequencing techniques could be utilized in clinical genetic screening of patients with PPGL. Somatic gain-of-function mutations in H-RAS are likely to contribute to disease pathogenesis. Analysing tumour DNA for somatic mutations in disease causing genes could provide relevant clinical information and have an impact on patient management. Concomitant mutations in PPGL may occur in exceptional cases and have a substantial impact on tumour biology and patient phenotype. And finally genetic heterogeneity is present between and within a majority of PPGL tumours.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1047
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-234285 (URN)978-91-554-9084-3 (ISBN)
Public defence
2014-12-06, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:15 (English)
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Available from: 2014-11-13 Created: 2014-10-15 Last updated: 2015-02-03

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Crona, JoakimVerdugo, Alberto DelgadoMaharjan, RajaniStalberg, PeterGranberg, DanHellman, PerBjörklund, Peyman

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