JOURNAL ARTICLE

Whole-Genome Sequencing of Growth Hormone (GH)-Secreting Pituitary Adenomas

Niko Välimäki, Hande Demir, Esa Pitkänen, Eevi Kaasinen, Atte Karppinen, Leena Kivipelto, Camilla Schalin-Jäntti, Lauri A Aaltonen, Auli Karhu
Journal of Clinical Endocrinology and Metabolism 2015, 100 (10): 3918-27
26280510

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.

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