Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab
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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.
KeywordsMBD4 Uveal melanoma Mutation Immunotherapy Predisposition gene
We are indebted to the patient and her family and acknowledge the contribution of Dr. Grant Cameron, along with the many clinicians and allied health professionals involved in her care. We are grateful to Dr. Robert Rawson, Dr. Michael Walsh, Dr. Ken Dutton-Regester, Dr. Lauren Aoude, Madeleine Howlie and Hayley Hamilton for input into this study.
The work was funded by the National Health and Medical Research Council of Australia (NHMRC 1093017). N.K.H. is supported by a fellowship from the NHMRC (1117663).
Compliance with ethical standards
Ethics approval was obtained from the Human Research Ethics Committees of the QIMR Berghofer Medical Research Institute. Written informed consent was obtained from the patient.
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