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

Manuel Rodrigues, Lenha Mobuchon, Alexandre Houy, Alice Fiévet, Sophie Gardrat, Raymond L. Barnhill, Tatiana Popova, Vincent Servois, Aurore Rampanou, Aurore Mouton, Stéphane Dayot, Virginie Raynal, Michèle Galut, Marc Putterman, Sarah Tick, Nathalie Cassoux, Sergio Roman-Roman, François-Clément Bidard, Olivier Lantz, Pascale Mariani, Sophie Piperno-Neumann and Marc-Henri Stern ()
Additional contact information
Manuel Rodrigues: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer
Lenha Mobuchon: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer
Alexandre Houy: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer
Alice Fiévet: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer
Sophie Gardrat: PSL Research University
Raymond L. Barnhill: PSL Research University
Tatiana Popova: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer
Vincent Servois: PSL Research University
Aurore Rampanou: PSL Research University, Laboratory of Circulating Tumor Biomarkers, SiRIC
Aurore Mouton: PSL Research University, INSERM CIC-BT 1428
Stéphane Dayot: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer
Virginie Raynal: PSL Research University, INSERM U830 and Institut Curie Genomics of Excellence (ICGex) Platform
Michèle Galut: PSL Research University, Biological Resource Center
Marc Putterman: Quinze-Vingts National Ophthalmology Hospital
Sarah Tick: Quinze-Vingts National Ophthalmology Hospital
Nathalie Cassoux: University of Paris Descartes
Sergio Roman-Roman: PSL Research University
François-Clément Bidard: PSL Research University
Olivier Lantz: PSL Research University, INSERM CIC-BT 1428
Pascale Mariani: PSL Research University
Sophie Piperno-Neumann: PSL Research University
Marc-Henri Stern: PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer

Nature Communications, 2018, vol. 9, issue 1, 1-6

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04322-5

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