SF3B1(R625H)突变导致ESRRG异常剪接促进泌乳素腺瘤发生发展机制的研究

泌乳素腺瘤是临床最常见的垂体肿瘤，耐药和侵袭性泌乳素腺瘤缺乏有效的治疗手段，预后不佳。在前期研究中，我们对227例患者采用全基因组测序联合数字PCR验证，在国际上率先发现了泌乳素腺瘤中的首个高频基因突SF3B1 R625H (突变率19.8%)，突变患者泌乳素水平较高而无进展生存期较短，提示该突变与泌乳素腺瘤的生长与增殖密切相关。通过转录组学可变剪接分析，我们发现剪切蛋白SF3B1突变可导致雌激素相关受体γ(ESRRG)异常剪接，并增强了ESRRG与垂体特异性转录因子1(Pit-1)的结合。本项目拟在前期工作基础上，针对SF3B1 R625H突变介导ESRRG可变剪接的分子机制进行深入研究，阐释该突变通过诱导产生ESRRG变异型转录本，从而促进泌乳素过量分泌及细胞过度增殖的内在机制。本研究将从全新角度揭示泌乳素腺瘤的潜在分子机制，并为泌乳素腺瘤的分子分类和个体化诊疗提供新的方向。

Prolactinomas is one of the most clinically occurring pituitary tumors, and its molecular genetic characteristics remain poorly understood. Here, we performed whole-genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validated 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 (SF3B1) R625H in 19.8% prolactinomas for the first time. Patients with the mutation had higher prolactin levels and shorter progression-free survival, suggesting that the mutation was closely related to the growth and proliferation of prolactinomas. SF3B1 is one of the most important alternative splicing proteins in vivo. Through alternative splicing analysis, we found that this mutation can lead to cryptic splicing of estrogen-associated receptor gamma (ESRRG) and enhance the binding of ESRRG to pituitary specific transcription factor 1(Pit-1). This project is intended to be based on the preliminary work, to conduct an in-depth study on the molecular mechanism of SF3B1 R625H mutation mediated alternative splicing of ESRRG, and explain the intrinsic mechanism by which the mutation induces the generation of cryptic ESRRG transcripts, thus promoting the excessive secretion of prolactin and cell proliferation. This study will reveal the underlying molecular pathologic mechanism of prolactinomas from a new perspective and may provide a new direction for the individualized diagnosis and treatment of prolactinomas.