Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.
Manuel J RodriguesLenha MobuchonAlexandre HouyAlice FiévetSophie GardratRaymond L BarnhillTatiana PopovaVincent ServoisAurore RampanouAurore MoutonStéphane DayotVirginie RaynalMichèle GalutMarc PuttermanSarah TickNathalie CassouxSergio Roman-RomanFrançois-Clément BidardOlivier LantzPascale MarianiSophie Piperno-NeumannMarc-Henri SternPublished in: Nature communications (2018)
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.
Keyphrases
- dna repair
- end stage renal disease
- squamous cell carcinoma
- small cell lung cancer
- ejection fraction
- skin cancer
- healthcare
- newly diagnosed
- chronic kidney disease
- copy number
- dna methylation
- prognostic factors
- peritoneal dialysis
- single cell
- quality improvement
- risk factors
- squamous cell
- pain management
- patient reported outcomes
- childhood cancer