Somatic SF3B1 hotspot mutation in prolactinomas

Chuzhong Li, Weiyan Xie, Jared S. Rosenblum, Jianyu Zhou, Jing Guo, Yazhou Miao, Yutao Shen, Hongyun Wang, Lei Gong, Mingxuan Li, Sida Zhao, Sen Cheng, Haibo Zhu, Tao Jiang, Shiying Ling, Fei Wang, Hongwei Zhang, Mingshan Zhang, Yanming Qu, Qi Zhang, Guilin Li, Junmei Wang, Jun Ma, Zhengping Zhuang () and Yazhuo Zhang ()
Additional contact information
Chuzhong Li: Capital Medical University
Weiyan Xie: Capital Medical University
Jared S. Rosenblum: National Institutes of Health
Jianyu Zhou: BNRIST, Tsinghua University
Jing Guo: Capital Medical University
Yazhou Miao: Capital Medical University
Yutao Shen: Capital Medical University
Hongyun Wang: Capital Medical University
Lei Gong: Capital Medical University
Mingxuan Li: Capital Medical University
Sida Zhao: Capital Medical University
Sen Cheng: Capital Medical University
Haibo Zhu: Capital Medical University
Tao Jiang: BNRIST, Tsinghua University
Shiying Ling: The First Affiliated Hospital of University of Science and Technology of China
Fei Wang: The First Affiliated Hospital of University of Science and Technology of China
Hongwei Zhang: Sanbo Brain Hospital, Capital Medical University
Mingshan Zhang: Sanbo Brain Hospital, Capital Medical University
Yanming Qu: Sanbo Brain Hospital, Capital Medical University
Qi Zhang: National Institutes of Health
Guilin Li: Capital Medical University
Junmei Wang: Capital Medical University
Jun Ma: Beijing Tiantan Hospital affiliated to Capital Medical University
Zhengping Zhuang: National Institutes of Health
Yazhuo Zhang: Capital Medical University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.

Date: 2020
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DOI: 10.1038/s41467-020-16052-8

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