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Elaine Michele Binkley, Colleen M Cebulla, Robert Pilarski, James B Massengill, Meghan J Marino, Arun D Singh, Mohamed H Abdel-Rahman; Lack of BAP1 germline gene mutation in patients with early onset uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5077.
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Germline mutations in the tumor suppressor gene BAP1 have been found to be important to the pathogenesis of uveal melanoma and an associated familial cancer syndrome. This BAP1 syndrome results in a predisposition to uveal melanoma, cutaneous melanoma, mesothelioma, and renal cell carcinoma. Early onset of uveal melanoma is a feature of hereditary cancer predisposition syndromes. This study aims to determine the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma, diagnosed before age 30. We hope to help better define risk factors for disease pathogenesis and risk for transmission to offspring in this subset of uveal melanoma patients.
Approval for this project was obtained from the Institutional Review Board of the Ohio State University. Peripheral blood samples were obtained from a series of 11 patients with early onset uveal melanoma (average age 22.6 years, range 3 months to 29 years). Germline DNA was extracted from peripheral blood leukocytes. BAP1 sequencing was then carried out using direct sequencing of all exons and adjacent intronic sequences.
All 11 patients were negative for pathogenic germline mutation in BAP1. One patient had an intronic variant of uncertain significance (c.123-48T>G). Similarly, family history of the most specific BAP1 syndrome cancers (uveal melanoma, mesothelioma, and renal cell carcinoma) was negative in all patients, while 2 families had family history of cutaneous melanoma. Other cancers present in the families included lymphoma, lung, breast, colon, pancreatic, cervical, uterine, ovarian, prostate, bone, and brain.
This work suggests that germline mutation in genes other than BAP1 likely play a greater role in the underlying genetic predisposition to early onset uveal melanoma. Future work will be directed at identifying additional genes which may be altered in these patients.
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