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; Marc-Henri Stern

doi:10.1038/s41467-018-04322-5

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

Nat Commun. 2018 May 14;9(1):1866. doi: 10.1038/s41467-018-04322-5.

Authors

Manuel Rodrigues^{1

2}, Lenha Mobuchon¹, Alexandre Houy¹, Alice Fiévet^{1

3}, Sophie Gardrat⁴, Raymond L Barnhill^{4

5}, Tatiana Popova¹, Vincent Servois⁶, Aurore Rampanou⁷, Aurore Mouton⁸, Stéphane Dayot¹, Virginie Raynal⁹, Michèle Galut¹⁰, Marc Putterman¹¹, Sarah Tick¹², Nathalie Cassoux^{5

13}, Sergio Roman-Roman¹⁴, François-Clément Bidard^{2

7

15}, Olivier Lantz⁸, Pascale Mariani¹⁶, Sophie Piperno-Neumann², Marc-Henri Stern^{17

18}

Affiliations

¹ Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, 75248, France.
² Department of Medical Oncology, Institut Curie, PSL Research University, Paris, 75248, France.
³ Department of Genetics, Institut Curie, PSL Research University, Paris, 75248, France.
⁴ Department of Biopathology, Institut Curie, PSL Research University, Paris, 75248, France.
⁵ Faculty of Medicine, University of Paris Descartes, Paris, 75006, France.
⁶ Department of Medical Imaging, Institut Curie, PSL Research University, Paris, 75248, France.
⁷ Institut Curie, PSL Research University, Laboratory of Circulating Tumor Biomarkers, SiRIC, Paris, 75248, France.
⁸ Institut Curie, PSL Research University, INSERM CIC-BT 1428, Paris, 75248, France.
⁹ Institut Curie, PSL Research University, INSERM U830 and Institut Curie Genomics of Excellence (ICGex) Platform, Paris, 75248, France.
¹⁰ Institut Curie, PSL Research University, Biological Resource Center, Paris, 75248, France.
¹¹ Department of Pathology, Quinze-Vingts National Ophthalmology Hospital, Paris, 75012, France.
¹² Department of Ophthalmology III, Quinze-Vingts National Ophthalmology Hospital, Paris, 75012, France.
¹³ Department of Ocular Oncology, Institut Curie, PSL Research University, Paris, 75248, France.
¹⁴ Department of Translational Research, Institut Curie, PSL Research University, Paris, 75248, France.
¹⁵ UVSQ, Paris Saclay University, Saint-Quentin, 78035, France.
¹⁶ Department of Surgical Oncology, Institut Curie, PSL Research University, Paris, 75248, France.
¹⁷ Institut Curie, PSL Research University, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, 75248, France. [email protected].
¹⁸ Department of Genetics, Institut Curie, PSL Research University, Paris, 75248, France. [email protected].

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antibodies, Monoclonal, Humanized / therapeutic use*
Antineoplastic Agents, Immunological / therapeutic use*
Atlases as Topic
CpG Islands
Endodeoxyribonucleases / genetics*
Endodeoxyribonucleases / immunology
Eye Enucleation
Female
Genome, Human
Germ-Line Mutation*
Humans
Loss of Heterozygosity
Lymphatic Metastasis
Melanoma / drug therapy
Melanoma / genetics*
Melanoma / immunology
Melanoma / surgery
Phenotype
Point Mutation
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Uveal Neoplasms / drug therapy
Uveal Neoplasms / genetics*
Uveal Neoplasms / immunology
Uveal Neoplasms / surgery

Substances

Antibodies, Monoclonal, Humanized
Antineoplastic Agents, Immunological
PDCD1 protein, human
Programmed Cell Death 1 Receptor
pembrolizumab
Endodeoxyribonucleases
MBD4 protein, human

Supplementary concepts

Uveal melanoma