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Cold Spring Harb Mol Case Stud. 2017 May;3(3):a001602. doi: 10.1101/mcs.a001602.

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Author information

1
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
2
Division of Endocrinology, Diabetes, and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
3
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
4
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
5
Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering, New York, New York 10065, USA.

Abstract

Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.

KEYWORDS:

adrenocorticotropic hormone excess; increased circulating ACTH level; increased circulating cortisol level; neoplasm of the anterior pituitary; neoplasm of the endocrine system; pituitary corticotropic cell adenoma

PMID:
28487882
PMCID:
PMC5411693
DOI:
10.1101/mcs.a001602
[Indexed for MEDLINE]
Free PMC Article

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