1. Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab.
- Author
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Johansson, Peter A., Stark, Andrew, Palmer, Jane M., Bigby, Kieron, Brooks, Kelly, Rolfe, Olivia, Pritchard, Antonia L., Whitehead, Kevin, Warrier, Sunil, Glasson, William, and Hayward, Nicholas K.
- Subjects
NONSENSE mutation ,UVEAL diseases ,IPILIMUMAB ,MELANOMA ,THERAPEUTICS ,BRAF genes - Abstract
There is currently no effective treatment for metastasised uveal melanoma (UM). Recently, it was reported that a UM patient was responsive to checkpoint inhibitor (CI) treatment, due to a high tumour mutation burden correlated with a germline loss-of-function MBD4 mutation. Here, we report on another UM patient who carried an MBD4 germline nonsense variant (p.Leu563Ter) and her tumour showed a fivefold higher than average mutation burden. We confirmed the association between germline loss-of-function variant in MBD4 and CI response. The patient experienced stable disease (10 months) and survived 2 years with metastatic disease, which is twice as long as median survival. Additionally, the frequency of MBD4 loss-of-function variants in reported UM cohorts was > 20 times higher than in an aggregated population genome database (P < 5 × 10
−5 ), implying a potential role as UM predisposition gene. These findings provide a strong basis for the inclusion of MBD4 in the screening of potential UM-prone families as well as stratification of immunotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2019
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