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Molecular Cancer Research
Molecular Cancer Research

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Cancer “-omics”

Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors

Niko Välimäki, Camilla Schalin-Jäntti, Atte Karppinen, Anders Paetau, Leena Kivipelto, Lauri A. Aaltonen and Auli Karhu
Niko Välimäki
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.Applied Tumor Genomics, Research Programs Unit, FI-00014 University of Helsinki, Finland.
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Camilla Schalin-Jäntti
Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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  • ORCID record for Camilla Schalin-Jäntti
Atte Karppinen
Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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Anders Paetau
Department of Pathology, HUSLAB, University of Helsinki, Helsinki, Finland.
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Leena Kivipelto
Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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Lauri A. Aaltonen
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.Applied Tumor Genomics, Research Programs Unit, FI-00014 University of Helsinki, Finland.
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Auli Karhu
Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.Applied Tumor Genomics, Research Programs Unit, FI-00014 University of Helsinki, Finland.
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  • For correspondence: auli.karhu@helsinki.fi
DOI: 10.1158/1541-7786.MCR-19-0434 Published December 2019
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Abstract

Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory Gα protein (Gαs encoded by GNAS) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone–secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were GNAS mutation negative (Gsp−). The chromosome stable (CS) –group contained Gsp+ somatotropinomas and two totally aneuploidy-free Gsp− tumors. Genes related to the mitotic G1–S-checkpoint transition were differentially expressed in CA- and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct Gsp genotype–specific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory Gα (Gαi) signaling is activated in Gsp+ tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp− somatotropinomas, whereas Gsp+ tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated Gαi signaling.

Implications: These findings provide valuable new information about subtype-specific pituitary tumorigenesis and may help to elucidate the mechanisms of aneuploidy also in other tumor types.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;17:2432–43

  • Received April 24, 2019.
  • Revision received July 25, 2019.
  • Accepted September 27, 2019.
  • Published first October 2, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Research: 17 (12)
December 2019
Volume 17, Issue 12
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Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors
Niko Välimäki, Camilla Schalin-Jäntti, Atte Karppinen, Anders Paetau, Leena Kivipelto, Lauri A. Aaltonen and Auli Karhu
Mol Cancer Res December 1 2019 (17) (12) 2432-2443; DOI: 10.1158/1541-7786.MCR-19-0434

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Genetic and Epigenetic Characterization of Growth Hormone–Secreting Pituitary Tumors
Niko Välimäki, Camilla Schalin-Jäntti, Atte Karppinen, Anders Paetau, Leena Kivipelto, Lauri A. Aaltonen and Auli Karhu
Mol Cancer Res December 1 2019 (17) (12) 2432-2443; DOI: 10.1158/1541-7786.MCR-19-0434
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