Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab

Peter A Johansson, Andrew Stark, Jane M Palmer, Kieron Bigby, Kelly Brooks, Olivia Rolfe, Antonia L Pritchard, Kevin Whitehead, Sunil Warrier, William Glasson, Nicholas K Hayward

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12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)433-436
Number of pages4
JournalImmunogenetics
Volume71
Issue number5-6
Early online date4 Feb 2019
DOIs
Publication statusPublished - 1 May 2019

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Keywords

  • Immunotherapy
  • MBD4
  • Mutation
  • Predisposition gene
  • Uveal melanoma

Cite this

Johansson, P. A., Stark, A., Palmer, J. M., Bigby, K., Brooks, K., Rolfe, O., ... Hayward, N. K. (2019). Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab. Immunogenetics, 71(5-6), 433-436. https://doi.org/10.1007/s00251-019-01108-x