Population-based analysis of BAP1 germline variations in patients with uveal melanoma
| Autor: | Tero Kivelä, Johannes E. Jäntti, Virpi Raivio, Joni A. Turunen, Martin Täll, Reetta-Stiina Järvinen, Salla Markkinen, Pauliina Repo |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Untranslated region Adult Male Uveal Neoplasms Adolescent DNA Copy Number Variations RNA Splicing Mutation Missense Biology Germline Cohort Studies 03 medical and health sciences Exon 0302 clinical medicine Cell Line Tumor Genetics Missense mutation Humans Genetic Predisposition to Disease Copy-number variation Molecular Biology Gene Melanoma Genetics (clinical) Finland Germ-Line Mutation Aged Aged 80 and over BAP1 Tumor Suppressor Proteins Intron General Medicine Exons Middle Aged Introns 3. Good health Pedigree 030104 developmental biology Germ Cells 030220 oncology & carcinogenesis Female Ubiquitin Thiolesterase |
| Zdroj: | Human molecular genetics. 28(14) |
| ISSN: | 1460-2083 |
| Popis: | Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish–Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3′ UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G>T) and exon 14 (c.1780_1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A>G) and 9 (c.680G>A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9/433 (2%) and 4/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS. |
| Databáze: | OpenAIRE |
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