Niko Välimäki1, Hande Demir1, Esa Pitkänen1, Eevi Kaasinen1, Atte Karppinen1, Leena Kivipelto1, Camilla Schalin-Jäntti1, Lauri A Aaltonen1, Auli Karhu1. 1. Department of Medical and Clinical Genetics (N.V.,H.D., E.P., E.K., L.A.A., A.Karh.), Genome-Scale Biology Research Programs Unit (N.V., H.D., E.P., E.K., L.A.A., A.Karh.), University of Helsinki, 00014 Helsinki, Finland; and Department of Neurosurgery (A.Karp., L.K.), Helsinki University Central Hospital, and Department of Endocrinology (C.S.-J.), Abdominal Center, University of Helsinki and Helsinki University Central Hospital, 00029 Helsinki, Finland.
Abstract
CONTEXT: The somatic landscape of pituitary adenomas is largely unknown. Identification of somatic alterations aims at better understanding of tumor pathology. OBJECTIVE: The objective of the study was a genome-wide characterization of somatic single-nucleotide variants, structural variants, and copy-number aberrations in somatotropinomas. DESIGN AND SETTING: Whole-genome sequencing and single-nucleotide polymorphism array analyses were performed on 12 fresh-frozen somatotropinomas and their corresponding blood samples. All the coding somatic variants were confirmed by Sanger sequencing. PATIENTS: Studied tumors were somatotropinomas. Apart from one AIP mutation-positive patient, all cases were mutation negative for the established germline mutations associated with pituitary adenomas. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Somatic variants were identified with an established computational pipeline and filtered against germline data. Somatic copy number alteration analyses were performed using segmentation-based approaches. RESULTS: A genome-wide analysis revealed on average 129 somatic single-nucleotide variants per tumor. Further analysis of coding regions showed on average 2.3 single-nucleotide variants per tumor. The only recurrent somatic events were the oncogenic GNAS mutation (p.Arg201Cys) and shared chromosome losses (chromosomes 1, 6, 13, 14, 15, 16, 18, 22). Analysis of somatic structural variants revealed one tumor with a complex chromosomal rearrangement. CONCLUSIONS: Somatotropinomas showed a low number of somatic genetic alterations. Whereas no novel recurrently mutated genes could be identified, the somatic landscape has potential to affect the Ca(2+) and ATP pathways known to be involved in the pituitary tumorigenesis. Further studies, eg, methylome and transcriptome analyses, are needed to investigate possible interplay between the recurrent chromosome losses and epigenetic factors.
CONTEXT: The somatic landscape of pituitary adenomas is largely unknown. Identification of somatic alterations aims at better understanding of tumor pathology. OBJECTIVE: The objective of the study was a genome-wide characterization of somatic single-nucleotide variants, structural variants, and copy-number aberrations in somatotropinomas. DESIGN AND SETTING: Whole-genome sequencing and single-nucleotide polymorphism array analyses were performed on 12 fresh-frozen somatotropinomas and their corresponding blood samples. All the coding somatic variants were confirmed by Sanger sequencing. PATIENTS: Studied tumors were somatotropinomas. Apart from one AIP mutation-positive patient, all cases were mutation negative for the established germline mutations associated with pituitary adenomas. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Somatic variants were identified with an established computational pipeline and filtered against germline data. Somatic copy number alteration analyses were performed using segmentation-based approaches. RESULTS: A genome-wide analysis revealed on average 129 somatic single-nucleotide variants per tumor. Further analysis of coding regions showed on average 2.3 single-nucleotide variants per tumor. The only recurrent somatic events were the oncogenic GNAS mutation (p.Arg201Cys) and shared chromosome losses (chromosomes 1, 6, 13, 14, 15, 16, 18, 22). Analysis of somatic structural variants revealed one tumor with a complex chromosomal rearrangement. CONCLUSIONS:Somatotropinomas showed a low number of somatic genetic alterations. Whereas no novel recurrently mutated genes could be identified, the somatic landscape has potential to affect the Ca(2+) and ATP pathways known to be involved in the pituitary tumorigenesis. Further studies, eg, methylome and transcriptome analyses, are needed to investigate possible interplay between the recurrent chromosome losses and epigenetic factors.
Authors: Wenya Linda Bi; Noah F Greenwald; Shakti H Ramkissoon; Malak Abedalthagafi; Shannon M Coy; Keith L Ligon; Yu Mei; Laura MacConaill; Matt Ducar; Le Min; Sandro Santagata; Ursula B Kaiser; Rameen Beroukhim; Edward R Laws; Ian F Dunn Journal: Endocrinology Date: 2017-07-01 Impact factor: 4.736
Authors: Scott Haston; Sara Pozzi; Gabriela Carreno; Saba Manshaei; Leonidas Panousopoulos; Jose Mario Gonzalez-Meljem; John R Apps; Alex Virasami; Selvam Thavaraj; Alice Gutteridge; Tim Forshew; Richard Marais; Sebastian Brandner; Thomas S Jacques; Cynthia L Andoniadou; Juan Pedro Martinez-Barbera Journal: Development Date: 2017-05-15 Impact factor: 6.868