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

• Published in: Nature communications Vol. 9; no. 1; pp. 1866 - 6
• Main Authors: Rodrigues, Manuel, Mobuchon, Lenha, Houy, Alexandre, Fiévet, Alice, Gardrat, Sophie, Barnhill, Raymond L., Popova, Tatiana, Servois, Vincent, Rampanou, Aurore, Mouton, Aurore, Dayot, Stéphane, Raynal, Virginie, Galut, Michèle, Putterman, Marc, Tick, Sarah, Cassoux, Nathalie, Roman-Roman, Sergio, Bidard, François-Clément, Lantz, Olivier, Mariani, Pascale, Piperno-Neumann, Sophie, Stern, Marc-Henri
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 45/23; 631/67/68; 692/4028/67/1484; Aged; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents, Immunological - therapeutic use; Atlases as Topic; Cancer; CpG Islands; Deactivation; Endodeoxyribonucleases - genetics; Endodeoxyribonucleases - immunology; Eye Enucleation; Female; Genome, Human; Genomes; Germ-Line Mutation; Heterozygosity; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Inactivation; Loss of Heterozygosity; Lymphatic Metastasis; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - immunology; Melanoma - surgery; Metastases; Metastasis; multidisciplinary; Mutation; PD-1 protein; Phenotype; Phenotypes; Point Mutation; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Science; Science (multidisciplinary); Tumors; Uveal Neoplasms - drug therapy; Uveal Neoplasms - genetics; Uveal Neoplasms - immunology; Uveal Neoplasms - surgery
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04322-5

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.