May 2018 - Outlier response to anti-PD1

Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. We think a lot more work needs to be done with OUTLIERS who get positive responses. We are only starting to get to grips with cancer with a long way still to go.

Abstract

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors.

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