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Research Paper|Volume 13, Issue 1|pp 1276—1293

Genomic and transcriptomic analysis of pituitary adenomas reveals the impacts of copy number variations on gene expression and clinical prognosis among prolactin-secreting subtype

Yiyuan Chen1, Hua Gao1, Weiyan Xie1, Jing Guo1, Qiuyue Fang1, Peng Zhao2, Chunhui Liu2, Haibo Zhu2, Zhuang Wang3, Jichao Wang4, Songbai Gui2,5,6, Yazhuo Zhang1,2,5,6, Chuzhong Li1,2,5,6
  • 1Department of Cell Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China
  • 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
  • 3Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
  • 4Department of Neurosurgery, People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang 830001, China
  • 5China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
  • 6Brain Tumor Center, Beijing Institute for Brain Disorders, Beijing 100070, China
Received: August 8, 2020Accepted: September 29, 2020Published: December 19, 2020
https://doi.org/10.18632/aging.202304

Copyright: © 2020 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Pituitary adenomas (PAs) are slow growing and benign primary intracranial tumors that often cause occupying effects or endocrine symptoms. PAs can be classified into various subtypes according to hormone secretion. Although widespread transcriptional alterations that cause aberrant hormone secretion have been characterized, the impact of genomic variations on transcriptional alterations is unclear due to the rare occurrence of single-nucleotide variations in PA. In this study, we performed whole-genome sequencing (WGS) on 76 PA samples across three clinical subtypes (PRL-PAs; GH-PAs, and NFPAs); transcriptome sequencing (RNA-seq) of 54 samples across these subtypes was also conducted. Nine normal pituitary tissues were used as controls. Common and subtype-specific transcriptional alterations in PAs were identified. Strikingly, widespread genomic copy number amplifications were discovered for PRL-PAs, which are causally involved in transcriptomic changes in this subtype. Moreover, we found that the high copy number variations (CNVs) in PRL-PA cause increased prolactin production, drug resistance and proliferative capacity, potentially through key genes with copy number amplification and transcriptional activation, such as BCAT1. This study provides insight into how genomic CNVs affect the transcriptome and clinical outcomes of PRL-PA and sheds light on the development of potential therapeutics for aberrantly activated targets.