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

• DOI: 10.1038/s41467-018-04322-5
• Publication Date: 2018-05-08T09:32:36Z
• Authors: 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 ...; Olivier Lantz; Pascale Mariani; Sophie Piperno-Ne...; Marc-Henri Stern
• Keywords: Uveal Neoplasms; 0301 basic medicine; Endodeoxyribonucleases; Genome, Human; Science; Q; Programmed Cell Death 1 Receptor; Loss of Heterozygosity; Antibodies, Monoclonal, Humanized; Article; Eye Enucleation; 3. Good health; 03 medical and health sciences; Antineoplastic Agents, Immunological; Atlases as Topic; Phenotype; Lymphatic Metastasis; Humans; Point Mutation; CpG Islands; Female; Melanoma; Germ-Line Mutation; Aged

Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present metastatic patient an exceptional high sensitivity to PD-1 inhibitor associated outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic inactivation in the tumor. We identify additional tumors The Cancer Genome Atlas (TCGA) cohorts similar hypermutator profiles patients carrying mutations loss heterozygosity. This MBD4-related phenotype may explain unexpected responses immune checkpoint inhibitors.