Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma

Harbour, J. William; Roberson, Elisha D.O.; Anbunathan, Hima; Onken, Michael D.; Worley, Lori A.; Bowcock, Anne M.

doi:10.1038/ng.2523

Cited by 468 publications

(437 citation statements)

References 13 publications

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“…Only one SF3B1 codon 625 mutation was identified in 26 tumors tested (3.8%), which is much lower than the percentage detected in primary tumors (18.6%) and consistent with the report that found SF3B1 mutations to be a good prognostic marker. 17 The SF3B1-mutant tumor was one of the three tumors that retained expression of BAP1…”

Section: Discussionmentioning

confidence: 99%

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Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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Uveal melanoma is the most common malignant tumor of the adult eye. Fifty percent of tumors will eventually metastasize, and there are no effective treatments for them. Recent studies of uveal melanoma have identified activating mutations in GNAQ and GNA11, loss-of-function mutations in the tumor suppressor gene BAP1, and recurrent mutations in codon 625 of SF3B1. Previous studies have reported the existence of a higher frequency of GNA11 than GNAQ mutations, frequent BAP1 loss, and rare SF3B1 mutations in metastatic uveal melanoma. We analyzed a cohort of 30 uveal melanoma metastases for the occurrence of GNAQ, GNA11, and SF3B1 mutations, as well as BAP1 loss, and correlated these parameters with clinical and histopathologic features. Most (92%) tumors were composed of cells with an epithelioid or mixed (o100% spindle cells) morphology. Tumor samples composed exclusively of spindle cells were rare (n ¼ 2, 8%). Most tumors showed a moderate to marked degree of nuclear pleomorphism (n ¼ 24, 96%), and contained hyperchromatic, vesicular nuclei with variably conspicuous nucleoli. GNA11 mutations were considerably more frequent than GNAQ mutations (GNA11, GNAQ, and wild-type in 18 (60%), 6 (20%), and 6 (20%) cases, respectively). SF3B1 mutation was found in 1 of 26 tumors (4%), whereas loss of BAP1 expression was present in 13 of 16 tumors (81%). Patients with GNA11-mutant tumors had poorer disease-specific survival (60.0 vs 121.4 months, P ¼ 0.03) and overall survival (50.6 vs 121.4 months, P ¼ 0.03) than those with tumors lacking GNA11 mutations. The survival data, combined with the predominance of GNA11 mutations in metastases, raises the possibility that GNA11-mutant tumors may be associated with a higher risk of metastasis and poorer prognosis than GNAQ-mutant tumors. Further studies of uveal melanoma are required to investigate the functional and prognostic relevance of oncogenic mutations in GNA11 and GNAQ.

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Section: Discussionmentioning

confidence: 99%

“…They were not detected in five metastases analyzed. 17 Described as a splice factor, SF3B1 was assumed to have a role in excising introns from premessenger RNA. Harbour et al 17 also proposed that the effect of SF3B1 mutation on tumorigenesis might be linked to an effect on chromatin remodeling.…”

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Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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“…A number of studies have identified frequent and recurrent somatic mutations in spliceosome machinery components such as SF3B1, ZRSR2, U2AF1, and SRSF2 in multiple cancer types. Of particular interest is SF3B1, which is frequently mutated in myelodysplastic syndrome, chronic lymphocytic leukemia (Quesada et al 2012), and uveal melanoma (Harbour et al 2013;Martin et al 2013). SF3B1 is a drug target for the small molecule spliceostatin A, generating hope that inhibiting SF3B1 may have therapeutic benefits.…”

Section: Discussionmentioning

confidence: 99%

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

Adler¹,

McCleland²,

Yee

et al. 2014

Genes Dev.

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The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the trisnRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. Highresolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.

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“…Importantly, these genes encode proteins that are all involved in 3 0 -splice site recognition during RNA splicing 4 . It has been shown that SF3B1 is mutated in a significant proportion (B20%) of uveal melanoma (UM), a rare malignant entity deriving from melanocytes from the uveal tract [5][6][7] , and in other solid tumours at lesser frequencies 8,9 .…”

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confidence: 99%

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

Alsafadi¹,

Houy²,

Battistella³

et al. 2016

European Journal of Cancer

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Hotspot mutations in the spliceosome gene SF3B1 are reported in B20% of uveal melanomas. SF3B1 is involved in 3 0 -splice site (3 0 ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3 0 ss. Modelling the differential junctions in SF3B1 WT and SF3B1 R625/K666 cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3'ss-sequence context. SF3B1 WT knockdown or overexpression do not reproduce the SF3B1 R625/K666 splice pattern, qualifying SF3B1 R625/K666 as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1 R625/K666 -promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.

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Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma

Cited by 468 publications

References 13 publications

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

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