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Mohamed H Abdel-Rahman, James B Massengill, Robert Pilarski, Frederick H Davidorf, Colleen M Cebulla; Study of the role of germline variants in MBD4 in predisposition to uveal melanoma and exceptional clinical outcomes.. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2829.
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© ARVO (1962-2015); The Authors (2016-present)
The vast majority of metastasis from uveal melanomas (UM) occur within the first 3 years after treatment of primary tumors. Once metastatic, UM is fatal within one year of diagnosis of metastasis in 78% of patients. Two recent reports showed that germline pathological variants in MBD4 are associated with rare cases of exceptional response to immunotherapy in metastatic UM. The goal of this study was to investigate the role of germline variants in MBD4 in predisposition to UM and exceptional clinical outcomes.
Frequency of germline pathogenic variants in MBD4 were assessed by whole exome sequencing or direct (Sanger) sequencing in UM patients with familial UM or exceptional clinical outcomes defined as patients developing metastasis > 72 months after treatment of primary tumors (long dormancy) and/or survived > 48 months after diagnosis of metastasis. Twenty five patients with familial UM and 13 patients with exceptional clinical outcomes were included.
We identified germline pathogenic variants in MBD4 in 0/25 of familial UM and 1/13 of UM with exceptional clinical outcomes. We also identified missense variants of uncertain significance in 2/25 (8%) of familial UM and 1/13 (7.7%) of UM patients with exceptional outcomes. The UM patients with pathogenic variant was a female diagnosed with UM at age 41 and presented with a large tumor 19.3 x 17.4 x 14.8 mm with monosomy of chromosome 3 and a somatic truncating mutation in BAP1. The tumor showed a very high mutation burden (398 somatic mutations). Patient was recurrence free at 76 months after enucleation. Family history of breast and colon cancers were reported in multiple first and second degree relatives.
Given the high frequency of germline pathogenic variants in MBD4 in non-cancer general population (1:1000) and the rarity in UM it is unlikely that it is a predisposition gene for UM. Pathogenic variants in MBD4 could be associated with prolonged survival even in patients with high-risk tumors. Additional unidentified germline/somatic events are likely associated with exceptional clinical outcomes in UM patients.
This is a 2020 ARVO Annual Meeting abstract.
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