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


METHODS
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.


METHODS
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.


METHODS
There were no interventions.


METHODS
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.
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.
Niko
N
Välimäki
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.
Hande
H
Demir
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.
Esa
E
Pitkänen
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.
Eevi
E
Kaasinen
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.
Atte
A
Karppinen
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.
Leena
L
Kivipelto
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.
Camilla
C
Schalin-Jäntti
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.
Lauri A
LA
Aaltonen
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.
Auli
A
Karhu
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D002864:Chromogranins; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D015894:Genome, Human; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs