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nature portfolio org/gatk/documentation/tooldocs/current/org_broadinstitute_gatk_tools_walkers_haplotypecaller_haplotypecaller org/gatk/documentation/tooldocs/current/org_broadinstitute_gatk_tools_walkers_cancer_m2_mutect2 privacy policy ccr7−/cd45ra+/cd8+ t-cells increased net/bowtie2/index advertising ccr7−/cd45ra+/cd8+ t-cells io/picard/ break-induced replication repair thermo fisher scientific methyl-cpg-binding protein 4 observations open avenues marc-henri stern social media inca prt-k14 umcure nature 464 nature 401 nature reprints wild-type allele due sophie piperno-neumann ophtalmologie des quinze-vingts françois-clément bidard library cancéropôle ile de-france costimulatory molecule-related signature formalin-fixed paraffin-embedded mismatch repair deficiency genome-wide association study ipilimumab pre-treated patients pan-cancer tcga series mbd4-related hypermutator phenotype intra-tumoral lymphocytic infiltrates fast gapped-read alignment received research grants brca1 germ-line mutations pembrolizumab-resistant subcutaneous metastasis psl research university merck research laboratory osteolytic bone lesions tcga research network permissions sergio roman-roman metastasis expressed pd-l1 gd glycosylase domain metastatic uveal melanoma nucleospin tissue kit tissue-agnostic approval author correspondence

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         headline:Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors
         description: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. Hypermutated tumors respond more favorably to checkpoint inhibitor-based immune therapy. Here, the authors describe a new hypermutated phenotype due to germline mutations and subsequent somatic loss of heterozygosity of MBD4, and a dramatic response to the PD-1 inhibitor pembrolizumab in a patient with a MBD4-inactivated hypermutated uveal melanoma.
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      headline:Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors
      description: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. Hypermutated tumors respond more favorably to checkpoint inhibitor-based immune therapy. Here, the authors describe a new hypermutated phenotype due to germline mutations and subsequent somatic loss of heterozygosity of MBD4, and a dramatic response to the PD-1 inhibitor pembrolizumab in a patient with a MBD4-inactivated hypermutated uveal melanoma.
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