The genomic profiling and MAMLD1 expression in human and canines with Cushing's disease

• Type of Material: Article
• Authors: Andrew Wang, University of California Los Angeles; Stewart Neill, Emory University; Scott Newman, St Jude Children's Research Hospital; Marianna A. Tryfonidou, Utrecht University; Adriana Ioachimescu, Emory University; Michael Rossi, Emory University; Bjorn P. Meij, Utrecht University; Nelson Oyesiku, Emory University
• Language: English
• Date: 2021-09-13
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12902-021-00845-z
• Title of Journal or Parent Work: BMC ENDOCRINE DISORDERS
• Volume: 21
• Issue: 1
• Start Page: 185
• End Page: 185
• Grant/Funding Information: Al Lerner Chair Award, Department of Neurosurgery, Emory University School of Medicine [AW, NMO], supported experimentation expenses.
• Keywords: MAMLD1; MUTATIONS; TARGET; HORMONE; COPY-NUMBER; TOPHAT; Pituitary adenomas; LARGE COHORT; Science & Technology; PITUITARY-ADENOMAS; PROOPIOMELANOCORTIN; DOGS; DIFFERENTIAL GENE; Endocrinology & Metabolism; Life Sciences & Biomedicine; Cushing's disease; Dog and man sequencing
• Research Categories: Biology, Genetics; Biology, Microbiology

Abstract

Background: Cushing’s disease (CD) is defined as hypercortisolemia caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (corticotroph PA) that afflicts humans and dogs. In order to map common aberrant genomic features of CD between humans and dogs, we performed genomic sequencing and immunostaining on corticotroph PA. Methods: For inclusion, humans and dog were diagnosed with CD. Whole exome sequencing (WES) was conducted on 6 human corticotroph PA. Transcriptome RNA-Seq was performed on 6 human and 7 dog corticotroph PA. Immunohistochemistry (IHC) was complete on 31 human corticotroph PA. Corticotroph PA were compared with normal tissue and between species analysis were also performed. Results: Eight genes (MAMLD1, MNX1, RASEF, TBX19, BIRC5, TK1, GLDC, FAM131B) were significantly (P < 0.05) overexpressed across human and canine corticotroph PA. IHC revealed MAMLD1 to be positively (3+) expressed in the nucleus of ACTH-secreting tumor cells of human corticotroph PA (22/31, 70.9%), but absent in healthy human pituitary glands. Conclusions: In this small exploratory cohort, we provide the first preliminary insights into profiling the genomic characterizations of human and dog corticotroph PA with respect to MAMLD1 overexpression, a finding of potential direct impact to CD microadenoma diagnosis. Our study also offers a rationale for potential use of the canine model in development of precision therapeutics.