Somatic SF3B1 hotspot mutation in prolactinomas
Somatic SF3B1 hotspot mutation in prolactinomas
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催乳素瘤中的体细胞 SF3B1 热点突变
DOI：
10.1038/s41467-020-16052-8
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发表时间：
2020-05-19
影响因子：
16.6
通讯作者：
Zhang, Yazhuo
中科院分区：
文献类型：
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作者：
Li, Chuzhong;Xie, Weiyan;Zhang, Yazhuo
泌乳素瘤的遗传基础和相应的临床相关性仍然知之甚少。在这里，我们对21例泌乳素瘤患者进行全基因组测序（WGS），以检测体细胞突变，然后对227例泌乳素瘤的组织样本进行数字聚合酶链反应（PCR）分析以验证突变。我们在19.8%的泌乳素瘤中发现了剪接因子3亚基B1（SF 3B 1 R625 H）的相同热点体细胞突变。与没有突变的患者相比，这些突变型泌乳素瘤患者显示出更高的泌乳素（PRL）水平（p = 0.02）和更短的无进展生存期（PFS）（p = 0.02）。此外，我们确定SF 3B 1 R625 H突变导致雌激素相关受体γ（ESRRG）的异常剪接，这导致垂体特异性正转录因子1（Pit-1）的结合更强，导致PRL分泌过多。因此，我们的研究验证了一个重要的突变，并阐明了潜在的机制，潜在的发病机制，催乳素瘤，可能会导致发展的靶向治疗。
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.