BAP1 Germline Mutations in Finnish Patients with Uveal Melanoma

Turunen, Joni A.; Markkinen, Salla; Wilska, R.; Saarinen, Silva; Raivio, Virpi; Tall, Martin; Lehesjoki, Anna‐Elina; Kivelä, Tero

doi:10.1016/j.ophtha.2016.01.008

Cited by 39 publications

(35 citation statements)

References 33 publications

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“…Our previous studies show that about 12% of UM manifest as a highly penetrant familial syndrome, often involving a variety of other cancers including cutaneous melanoma (CM) 4 5 , suggesting that genetic susceptibility likely plays an important role in the etiology of UM. Despite this, currently known highly penetrant germline mutations in BAP1, CDKN2A , or BRCA2 explain only about 3% of UM population-specific risk 6 7 8 9 . Thus, developing clinically relevant UM risk prediction models that account for both genetic and host factors is currently difficult, also because of a vastly unexplored role of low-penetrant genetic risk factors in the general UM population.…”

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confidence: 96%

Genetic markers of pigmentation are novel risk loci for uveal melanoma

Ferguson

Vogelsang

Ucisik-Akkaya

et al. 2016

Sci Rep

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While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415–0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419–0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339–0.637; p = 3.04E-07) are correlated (r2 > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.

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confidence: 96%

Genetic markers of pigmentation are novel risk loci for uveal melanoma

Ferguson

Vogelsang

Ucisik-Akkaya

et al. 2016

Sci Rep

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“…20 However, a germline BAP1 splice-site variant (c.67-1G>T) has been previously reported in a patient with metastatic uveal melanoma and prior diagnosis of bladder cancer. 21 Of note, RNA and/or protein analysis were not performed to confirm a null effect, and thus these findings must be interpreted with caution. 14 In addition, this study only sequenced the BAP1 gene in germline DNA, and somatic alterations were not investigated using NGS or tissue-specific IHC.…”

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confidence: 97%

Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer

et al. 2020

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Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (TPDS). BAP1 TPDS is associated with an increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma, and several other cancer subtypes. Here, we report a germline nonsense BAP1 variant (c.850G>T, p.Glu284Ter) in a patient with bladder cancer and a strong family history of malignancy. Concurrently, we identified a somatic frameshift BAP1 variant, and as expected, immunostaining validated the loss of BAP1 protein in patient-derived tumor specimens. Together, these data provide strong evidence of pathogenicity in this case. With the addition of bladder cancer to the tumor types reported with germline BAP1 mutations, our understanding of the BAP1 TPDS continues to evolve, and may affect future screening and surveillance guidelines.

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“…One tested positive for a variant of uncertain significance in BRCA2, and both tested negative for BAP1 gene mutations. The studied incidence of BAP1 mutation in uveal melanoma has been calculated to range from 1.6 to 3.2% in different populations [35][36][37]. In calculating this incidence rate, Aoude et al [37] screened both unilateral and bilateral uveal melanoma cases, but whether or not any bilateral cases possessed a BAP1 mutation was not mentioned.…”

Section: Discussionmentioning

confidence: 99%

Multiple Uveal Melanoma

Kheir

Kim

Materin³

2020

Ocul Oncol Pathol

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Introduction: Multiple uveal melanoma is a rare occurrence and includes bilateral melanoma, unilateral multiple/multifocal melanoma, or melanoma with metastasis to the ipsilateral or contralateral eye. Methods: A chart review of patients diagnosed with uveal melanoma between January 2013 and January 2019 at the Duke University Eye Center Ophthalmic Oncology Service was performed. Results: Three patients with multiple, sequential melanoma were identified; patient 1 had bilateral choroidal melanoma and patients 2 and 3 had 2 choroidal melanomas occurring in the same eye. In all 3 patients, both the first and sequential choroidal melanomas were treated with I-125 radioactive plaque brachytherapy (PBT). Two patients were found to have developed secondary metastatic uveal melanoma as a presenting sign of systemic metastases. Patient 4, initially treated with PBT, was diagnosed with ipsilateral metastatic choroidal melanoma, also treated with PBT. Patient 5 had right eye enucleation for choroidal melanoma and developed vision-threatening me-tastasis in the left eye, which was treated with PBRT. None of the patients had history of cancer prior to their first diagnosis. Patients 1 and 5 were tested with a systemic melanoma panel; both were negative for BAP1, but patient 1 had a variant of unknown significance in BRCA2. Patient 3 had oculodermal melanocytosis, an established risk factor of uveal melanoma. Conclusion: Although rare, the possibility of multiple uveal melanoma does exist. Examination of the treated and contralateral eye on a regular basis is crucial, not only to identify local failure but also new metastases from the primary tumor and additional primary tumors.

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BAP1 Germline Mutations in Finnish Patients with Uveal Melanoma

Abstract: The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations.

Cited by 39 publications

References 33 publications

Genetic markers of pigmentation are novel risk loci for uveal melanoma

Genetic markers of pigmentation are novel risk loci for uveal melanoma

Concurrent germline and somatic pathogenic BAP1 variants in a patient with metastatic bladder cancer

Multiple Uveal Melanoma

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