David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
College of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
BMC Endocr Disord. 2021 Sep 13;21(1):185. doi: 10.1186/s12902-021-00845-z.
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.
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.
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.
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.
库欣病（CD）是由促肾上腺皮质激素（ACTH）分泌性垂体腺瘤（促皮质素 PA）引起的皮质醇增多症，影响人类和犬类。为了绘制人类和犬类 CD 之间常见的异常基因组特征图谱，我们对促皮质素 PA 进行了基因组测序和免疫染色。
纳入的人类和犬类均被诊断为 CD。对 6 例人类促皮质素 PA 进行全外显子组测序（WES）。对 6 例人类和 7 例犬类促皮质素 PA 进行转录组 RNA-Seq。对 31 例人类促皮质素 PA 进行免疫组化（IHC）。比较促皮质素 PA 与正常组织，并进行种间分析。
8 个基因（MAMLD1、MNX1、RASEF、TBX19、BIRC5、TK1、GLDC、FAM131B）在人类和犬类促皮质素 PA 中均显著过表达（P<0.05）。IHC 显示 MAMLD1 在人类促皮质素 PA 的 ACTH 分泌肿瘤细胞的核内呈阳性（3+）表达（22/31，70.9%），但在健康的人类垂体中不存在。
在这个小的探索性队列中，我们首次初步了解了人类和犬类促皮质素 PA 的基因组特征分析，发现了 MAMLD1 过表达，这可能对 CD 微腺瘤的诊断有直接影响。我们的研究还为犬类模型在开发精准治疗中的潜在应用提供了依据。
