Uveal Melanomas with SF3B1 Mutations

Yavuzyigitoglu, Serdar; Koopmans, Anna E; Verdijk, Robert M.; Vaarwater, Jolanda; Eussen, Bert; Bodegom, Alice van; Paridaens, Dion; Kılıç, Emine; Klein, Annelies de

doi:10.1016/j.ophtha.2016.01.023

Cited by 216 publications

(151 citation statements)

References 33 publications

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“…Not observed in our cohort, due to relatively short follow-up times, was the association between D3-UM with an EIF1AX versus SF3B1 mutation and low versus intermediate risk of developing metastatic disease compared with M3-UM (Yavuzyigitoglu et al, 2016). The distinct SCNA and DNA methylation profiles we observe in EIF1AX - versus SF3B1 -mutant D3-UM may contribute to the different prognoses associated with these mutually exclusive mutations.…”

Section: Discussionmentioning

confidence: 62%

“…Currently either disomy 3 (D3) versus M3 status or a 12-gene microarray-based gene expression panel is used to determine whether a patient is in a low- or a high-risk prognostic group (Harbour, 2014; Tschentscher et al, 2003). Recent analysis of a large D3-UM cohort showed SF3B1 mutation to be associated with an intermediate risk of developing later-onset metastatic UM (Yavuzyigitoglu et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

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Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson¹,

Shih²,

Yau³

et al. 2017

Cancer Cell

692

712

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SUMMARY Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1 -mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low-versus intermediate-risk clinical mutation subtypes.

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Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson¹,

Shih²,

Yau³

et al. 2017

Cancer Cell

692

712

View full text Add to dashboard Cite

show abstract

“…SF3B1 mutations have previously been associated with D3-UM with late onset metastasis [22]. In our cohort, 5/25 cases (20%) with SF3B1 mutations died of metastatic UM at the time of study closure.…”

Section: Sf3b1 Mutations In M3 Ummentioning

confidence: 59%

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

Thornton

Coupland

Olohan

et al. 2020

Cancers

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Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk. To gain further insight into the molecular landscape of UM, we designed a targeted next-generation sequencing (NGS) panel to detect SCNA and mutations in routine clinical UM samples. We compared hybrid-capture and amplicon-based target enrichment methods and tested a larger cohort of primary UM samples on the best performing panel. UM clinical samples processed either as fresh-frozen, formalin-fixed paraffin embedded (FFPE), small intraocular biopsies or following irradiation were successfully profiled using NGS, with hybrid capture outperforming the PCR-based enrichment methodology. We identified monosomy 3 (M3)-UM that were wild-type for BAP1 but harbored SF3B1 mutations, novel frameshift deletions in SF3B1 and EIF1AX, as well as a PLCB4 mutation outside of the hotspot on exon 20 coinciding with a GNAQ mutation in some UM. We observed samples that harboured mutations in both BAP1 and SF3B1, and SF3B1 and EIF1AX, respectively. Novel mutations were also identified in TTC28, KTN1, CSMD1 and TP53BP1. NGS can simultaneously assess SCNA and mutation data in UM, in a reliable and reproducible way, irrespective of sample type or previous processing. BAP1 and SF3B1 mutations, in addition to 8q copy number, are of added importance when determining UM patient outcome.

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“…These other factors included epithelioid cell morphology, high mitotic count, large tumour size, 8q gain, ciliary body involvement, and extraocular growth 3.The remaining case, however, is unusual in that it was D3 with clinical and histological features of a low metastatic risk tumour. Previous studies have suggested that D3 UM with a mutation in splicing Factor 3B Subunit 1A ( SF3B1 ) have an increased risk of developing metastases 52. Further studies are necessary to determine whether such a mutation is present in this particular case.…”

Section: Discussionmentioning

confidence: 99%

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Farquhar

Thornton

Coupland

et al. 2017

The Journal of Pathology CR

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Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow‐up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1‐positiveM3 UMs were associated with prolonged survival compared to nBAP1‐negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing ‘predominantly diffuse’ in most nBAP1‐negative UM, a distinct ‘focal perinuclear’ expression pattern – localized immediately adjacent to the cis Golgi – was seen in 31% (18/59). These tumours tended to carry loss‐of‐function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non‐genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1‐negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.

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Uveal Melanomas with SF3B1 Mutations

Cited by 216 publications

References 33 publications

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

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