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Mohamed H. Abdel-Rahman, Robert Pilarski, Colleen M. Cebulla, Andrew W. Stacey, James B. Massengill, Frederick H. Davidorf; Candidate Gene Testing In Uveal Melanoma Patients With Relative High-risk For Hereditary Cancer Predisposition. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3335.
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© ARVO (1962-2015); The Authors (2016-present)
A subset of Uveal Melanoma (UM) has high risk for hereditary cancer predisposition. Little is known about potential candidate genes associated with increased risk of UM and other cancers in these patients. The aim of this study was to identifying the frequency of alterations in different potential candidate genes in UM patients with increased hereditary cancer risk.
A total of 55 unrelated UM patients with high-risk for hereditary cancer were studied including five patients with a family history of UM. Germline mutational screening of BAP1, CDKN2A, p14ARF, and exon 2 of CDK4 was carried out by direct sequencing in 55 patients and GNAQ was tested in 45 patients. In addition six patients with high risk for breast cancer were clinically tested for germline mutation in BRCA2. Linkage analysis to the previously reported 9q21 chromosomal region was carried out in two families with multiple individuals with different cancers.
We identified a truncating mutation in BAP1 in a single patient with strong family history of UM and other cancers. Cancers identified in individuals with germline BAP1 mutation in that family included UM, lung adenocarcinoma, cutaneous melanoma, mesothelioma, abdominal carcinoma (likely ovarian), meningioma and neuroendocrine carcinoma. Three additional UM patients from different families had BAP1 variants of unknown significance. In addition a variant of uncertain significance in exon 1b of p14ARF was detected in a UM patient and his mother who also had UM. We did not identify pathogenic mutations in CDKN2A, GNAQ, BRCA2 or exon 2 of CDK4 gene. Linkage analysis using markers from the 9q21 region showed negative LOD scores in all markers tested ruling out this region in the two families studied.
Our study supports the low frequency of germline mutation in BAP1 in UM patients with high risk for hereditary cancer. It also suggests that several candidate genes such as CDKN2A, GNAQ and CDK4 contribute very little if any role in hereditary cancer predisposition of UM patients. Further studies of the phenotype of patients and families with germline BAP1 mutation are warranted.
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