Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors

Nature Communications
Manuel RodriguesMarc-Henri Stern

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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Datasets Mentioned

BETA
EGAS00001002761

Methods Mentioned

BETA
deamination
glycosylase
RNA-seq
PCR

Clinical Trials Mentioned

NCT02849145
NCT02866149

Software Mentioned

ANNOVAR
MuTect2
Alamut Visual Software
NNSPLICE
GenomicAlignments
R
SAMtools mpileup
Flow Jo
Integrative Genomics Viewer ( IGV )
HaplotypeCaller

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