Somatic SF3B1 hotspot mutation in prolactinomas

Chuzhong Li,Hongwei Zhang,Shiying Ling,Weiyan Xie,Hongyun Wang,Jared S Rosenblum,Mingshan Zhang,Sen Cheng,Jing Guo,Fei Wang,Yanming Qu,Haibo Zhu,Mingxuan Li,Yutao Shen,Zhengping Zhuang,Yazhou Miao,Jianyu Zhou,Guilin Li,Junmei Wang,Sida Zhao,Lei Gong,Qi Zhang,Jun Ma,Tao Jiang,Yazhou Zhang

doi:10.1038/s41467-020-16052-8

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.

Highlights

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood
Cryptic estrogen related receptor gamma (ESRRG) resulted in a significant augment of PRL secretion (Supplementary Fig. 11). These results indicate that the cryptic ESRRG, resulting from SF3B1R625H contributes to an excess of PRL activation in prolactinomas, beyond physiologic with the canonical ESRRG in the pituitary
The driving genetic events that contribute to prolactinoma tumorigenesis remain unknown

Summary

Introduction

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. 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. We demonstrate that the identified mutation of SF3B1 results in aberrant splicing of ESRRG—a member of the estrogen receptor-related receptor (ESRR) family—leading to abnormal PRL secretion and tumorigenesis in prolactinomas. This finding may represent a distinct genotype of prolactinomas with unique clinical implications and contributes to the understanding of the molecular mechanism of prolactinomas

Methods

Results

Conclusion