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Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma

Cole, Yasemin C; Zhang, Yu-Zhi; Gallo, Beatrice; Januszewski, Adam P; Nastase, Anca; Essex, David J; Thaung, Caroline MH; ... Bowcock, Anne M; + view all (2022) Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma. Cancers , 14 (17) , Article 4105. 10.3390/cancers14174105. Green open access

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Abstract

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with <10% cytoplasmic BAP1 (cBAP1). Tumors exhibited heterogeneity with respect to BAP1 staining with different percentages of nBAP1 loss: ≥25% loss of nuclear BAP1 (nBAP1) was superior to chr8q and LOH3 as a prognostic indicator. Of the successfully sequenced UMs, 38% harbored oncogenic mutations in GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.

Type: Article
Title: Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/cancers14174105
Publisher version: https://doi.org/10.3390/cancers14174105
Language: English
Additional information: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: uveal melanoma; biomarkers; survival; metastasis; BAP1; SF3B1; EIF1AX; monosomy 3; immunohistochemistry; nonsense-mediated decay
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10155226
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