Somatic SF3B1 hotspot mutation in prolactinomas

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

doi:10.1038/s41467-020-16052-8

Cited by 52 publications

(55 citation statements)

References 28 publications

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“…A single patient with a de novo missense germline NR3C1 mutation associated with an ACTH-PA has also been described ( 138 ), while a child with corticotroph adenoma and partial glucocorticoid resistance had no detectable NR3C1 mutation ( 140 ). A recent study reported a novel somatic recurrent (“hotspot”) mutation in splicing factor 3 subunit B1 (p.R625H in SF3B1 ) in about 20% of prolactinomas in altogether 227 prolactinomas ( 141 ). This variant causes aberrant splicing of the estrogen related receptor gamma (ESRRG), causing stronger activation of PIT-1 leading to prolactin secretion and lactotroph proliferation.…”

Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

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Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Nadhamuni

Korbonits

2020

Endocrine Reviews

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Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or non-syndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and non-coding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multi-omics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis.

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Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

“…This is consistent with their generally low proliferation rate. Only a handful of genes show recurrent mutations ( 120 , 141 , 169 ). Such recurrently mutated genes are reported in more detail in Table 3 .…”

Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Nadhamuni

Korbonits

2020

Endocrine Reviews

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“…These mutations are also present in 20% of patients with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) [ 41 ] and in 15% of patients with chronic myeloid leukemia (CLL) [ 58 – 60 ] . More recently, SF3B1 mutations have been identified at relatively high frequency in some solid tumors, such as various pigmented tumors, including uveal melanoma (UM) [ 61 , 62 ], mucosal melanoma [ 63 ], leptomeningeal melanoma [ 64 ] and blue nevus-like cutaneous melanoma [ 65 ], and neuroblastomas that arise following chromothripsis [ 66 ], estrogen receptor-positive breast cancers (BC) [ 67 ], pancreatic ductal adenocarcinoma [ 68 ], prostate cancer [ 69 ], prolactinomas [ 70 ], acute myeloid leukemia [ 71 , 72 ], and many others [ 73 – 75 ].…”

Section: Sf3b1 Mutations In Cancermentioning

confidence: 99%

The biological function and clinical significance of SF3B1 mutations in cancer

et al. 2020

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Spliceosome mutations have become the most interesting mutations detected in human cancer in recent years. The spliceosome, a large, dynamic multimegadalton small nuclear ribonucleoprotein composed of small nuclear RNAs associated with proteins, is responsible for removing introns from precursor mRNA (premRNA) and generating mature, spliced mRNAs. SF3B1 is the largest subunit of the spliceosome factor 3b (SF3B) complex, which is a core component of spliceosomes. Recurrent somatic mutations in SF3B1 have been detected in human cancers, including hematological malignancies and solid tumors, and indicated to be related to patient prognosis. This review summarizes the research progress of SF3B1 mutations in cancer, including SF3B1 mutations in the HEAT domain, the multiple roles and aberrant splicing events of SF3B1 mutations in the pathogenesis of tumors, and changes in mutated cancer cells regarding sensitivity to SF3B small-molecule inhibitors. In addition, the potential of SF3B1 or its mutations to serve as biomarkers or therapeutic targets in cancer is discussed. The accumulated knowledge about SF3B1 mutations in cancer provides critical insight into the integral role the SF3B1 protein plays in mRNA splicing and suggests new targets for anticancer therapy.

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“…Mario et al found gonadotroph signatures in some corticotroph and somatotroph PitNETs by integrated pangenomic analyses [4]. The low mutation burdens of PitNETs based on WGS suggesting a limited impact of SNVs on the PitNET classi cations [20,29,30]. In this study, we found that expression at the DLK1/MEG3 locus played a key role in the differentiation of PitNETs in patients depending on the level of PIT1, and we suggested that DLK1 may be used in addition to the current array of PitNET classi cations.…”

Section: Discussionmentioning

confidence: 99%

The DLK1/MEG3 Locus is Related to the Differentiation of Pituitary Neuroendocrine Tumors

Chen

Gao

Liu

et al. 2020

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Background: Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs according to the 2017 WHO classification of tumors of endocrine organs. However, for a substantial proportion of PitNETs, the etiology is poorly understood.Methods: To analyze the diversity genes and pathways based on transcriptomic data of 172 patients by transcriptome sequencing, difference, correlation, and enrichment analysis. The transcriptomic data and clinical characteristics are applied to find the clinical significance of key genes by correlation analysis and ROC curve. Series functional experiments demonstrated the role of DLK1/MEG3 locus through antibody blocking and RNA interference in GH3, MMQ and ATT20 cell line.Results: In this study, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. As being specific feature change in somatotroph adenomas compared with other subtype adenomas, DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) PitNET patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph differentiation or lactotroph differentiation in PIT1(+) PitNET patients. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 domain significantly induced the synthesis and secretion of growth hormone/insulin-like growth factor-1 (GH/IGF-1) and inhibited cell growth and colony formation and that the loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines. There was a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line, regardless of whether anti-DLK1 monoclonal antibody blockade or siMEG3 was used. Conclusions: These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs in patients depending on the level of PIT1. In addition, these findings provide potential molecular target data for patient stratification and treatment in the future.

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Somatic SF3B1 hotspot mutation in prolactinomas

Cited by 52 publications

References 28 publications

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

The biological function and clinical significance of SF3B1 mutations in cancer

The DLK1/MEG3 Locus is Related to the Differentiation of Pituitary Neuroendocrine Tumors

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