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

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Listed:
  • 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
    PSL Research University)

  • 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
    PSL Research University)

  • Sophie Gardrat

    (PSL Research University)

  • Raymond L. Barnhill

    (PSL Research University
    University of Paris Descartes)

  • 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
    PSL Research University)

  • Sergio Roman-Roman

    (PSL Research University)

  • François-Clément Bidard

    (PSL Research University
    PSL Research University, Laboratory of Circulating Tumor Biomarkers, SiRIC
    Paris Saclay 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
    PSL Research University)

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.

Suggested Citation

  • Manuel Rodrigues & Lenha Mobuchon & Alexandre Houy & Alice Fiévet & Sophie Gardrat & Raymond L. Barnhill & Tatiana Popova & Vincent Servois & Aurore Rampanou & Aurore Mouton & Stéphane Dayot & Virgini, 2018. "Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors," Nature Communications, Nature, vol. 9(1), pages 1-6, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04322-5
    DOI: 10.1038/s41467-018-04322-5
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    Cited by:

    1. André Bortolini Silveira & Alexandre Houy & Olivier Ganier & Begüm Özemek & Sandra Vanhuele & Anne Vincent-Salomon & Nathalie Cassoux & Pascale Mariani & Gaelle Pierron & Serge Leyvraz & Damian Rieke , 2024. "Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Mischan Vali-Pour & Solip Park & Jose Espinosa-Carrasco & Daniel Ortiz-Martínez & Ben Lehner & Fran Supek, 2022. "The impact of rare germline variants on human somatic mutation processes," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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