Population-based analysis of BAP1 germline variations in patients with uveal melanoma

Abstract

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.

Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review

“…BAP1 mutations are infrequent in the general population and there are no homozygotes [ 36 , 37 ]. However, their frequency has been reported as 1–2% for UM, 0.5% for CM and 0–7% for MM in distinct cases, rising up to 25%, 0.7% and 20%, respectively, in familial cases [ 4 , 7 , 36 , 38 , 39 , 40 , 41 ]. Patients carrying BAP1 genetic variations were shown to have a higher incidence of peritoneal versus pleural MM [ 7 ].…”

Families with BAP1-Tumor Predisposition Syndrome in The Netherlands: Path to Identification and a Proposal for Genetic Screening Guidelines

“…In 28 families with multiple members affected by RCC, but without pathogenic variants in the Von Hippel–Lindau gene, no pathogenic variants were found in BAP1 [71]. Possible deep intronic variants in the BAP1 gene, not detectable with standard diagnostic techniques, might be present in a small subset [25]. Other candidate susceptibility genes have been mentioned for most BAP1-TPDS-associated tumors.…”

“…The occurrence of loss of function variants of BAP1 in the general population is extremely low, with only 12 variants noted in gnomAD and the absence of homozygotes [22]. However, frequency of this dominantly inherited cancer syndrome has been reported as 1–2% of UMs [23,24,25], 0.5% of CMs [26], and 0–7% of MMes in unselected cases [8,27,28,29,30,31]. The detection of pathogenic variants in BAP1 increases to up to 25%, 0.7%, and 20% when examining familial UM [24], CM [32], and MMe [33], respectively.…”

Human Organ‐Specific 3D Cancer Models Produced by the Stromal Self‐Assembly Method of Tissue Engineering for the Study of Solid Tumors

“…The most common age at diagnosis is 50-60 years, and the incidence is highest among people with lighter skin, fair hair, and blue eyes [210]. Familial cases and germline mutations are rare in UM [211,212]. Key chromosomal abnormalities and driver mutations, as well as the DecisionDx®-UM gene expression profile test allow classifying UM patients at low or high risk of metastasis [213].…”