Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

Purpose: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations.

Design: Retrospective case series from academic referral centers.

Participants: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene.

Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and GNA11 Mutations.

Purpose: The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM). However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM.

Methods: Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM.

Germline large deletion of BAP1 and decreased expression in non-tumor choroid in uveal melanoma patients with high risk for inherited cancer.

Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation. This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation. One hundred seventy-two UM patients with high risk of hereditary cancer were included.

Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1-tumor predisposition syndrome is underreported in cancer patients.

The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects).

Germline BAP1 alterations in familial uveal melanoma.

Uveal melanoma (UM) is the most commonly diagnosed primary intraocular tumor in adults. Familial UM (FUM), defined as two or more family members diagnosed with UM, is rare and estimated at less than 1% of all UM. Currently, BAP1 is the only gene known to contribute significant risk for UM.

Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients.

Background: To evaluate the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma (UM), diagnosed before age 30.

Materials And Methods: The study was carried out on 14 young uveal melanoma patients (average age 21.4 years, range 3 months to 29 years).

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1.

Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.

Objective: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer.

Design: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing.

Melanoma candidate genes CDKN2A/p16/INK4A, p14ARF, and CDK4 sequencing in patients with uveal melanoma with relative high-risk for hereditary cancer predisposition.

The reported frequencies of germline mutations in the melanoma candidate genes are low in patients with uveal melanoma (UM). However, the number of families studied is limited and the majority of the published reports used low-sensitivity techniques for mutational screening. Identifying the frequency of alterations in any of the melanoma genes in patients with UM with increased hereditary cancer risk is important for proper counseling of these patients.

Lack of GNAQ germline mutations in uveal melanoma patients with high risk for hereditary cancer predisposition.

A high frequency of somatic mutation in GNAQ has been reported in uveal melanoma (UM). GNAQ is located in the chromosomal band 9q21, the same chromosomal band that harbors a putative candidate gene for hereditary UM. We investigated the frequency of germline sequence alterations in the GNAQ gene in UM patients with increased predisposition to hereditary cancer.

Investigation of the potential utility of a linomide analogue for treatment of choroidal neovascularization.

The aim of this study was to test the selectivity, in-vivo effectiveness, and potential mechanism of action of a linomide analogue (N-phenyl-1,2-dihydro-4-hydroxyl-2-oxo-quinoline-3-carboxamide, Lin05) for inhibition of choroidal neovascularization. The selectivity of Lin05 was tested in cell proliferation assays with human umbilical vein endothelial cells (HUVEC) and a retinal pigmented epithelial cell line(ARPE-19). In-vivo anti-angiogenic effect of Lin05 was investigated utilizing an experimental laser-induced choroidal neovascularization (ECNV) model in adult Brown Norway rats.