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Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration

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Abstract

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.

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Acknowledgements

This work was supported by the LYric Grant INCa-DGOS-4664, by the Ligue Contre le Cancer Comité du Rhône and Comité de Savoie, and by a grant from Fondation ARC pour la recherche sur le cancer. The funding sources had no role in the study design, in the collection, analysis, and interpretation of data and in the writing of the manuscript. We thank NeuroBioTec Hospices Civils de Lyon BRC (France, AC-2013-1867, NFS96-900) for banking blood DNA samples. We thank Boehringer Ingelheim and the investigators of the AGO/GINECO group for providing control ovarian cancer specimens from the AGO-OVAR12 ancillary study. We thank M. Aguera for collecting samples and the PHENOCAN platform (ANR-11-EQPX-0035 PHENOCAN) for access to the Zeiss Axio San.Z1 slide scanner. We also thank D. Meyronet from the Pathology Department of Hospices Civils de Lyon for his expertise and for providing cerebellum samples, and M.-E. Mayeur, L. Odeyer, A. Colombe, A.-L. Pinto and J. Berthet for expert technical assistance in IHC/IF staining. We thank Doctor N. Chopin (Centre Leon Berard, Lyon) for his collaboration. We gratefully acknowledge Philip Robinson for English language editing (Direction de la Recherche Clinique, Hospices civils de Lyon).

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  1. Mathilde Small, Isabelle Treilleux, Coline Couillault, Bertrand Dubois, Jérôme Honnorat and Virginie Desestret contributed equally.

Authors and Affiliations

  1. Institut NeuroMyogène, Equipe Synaptopathies et Autoanticorps (SynatAc), INSERM U1217/UMR CRS 5310, Lyon, France

    Mathilde Small, Véronique Rogemond, Jérôme Honnorat & Virginie Desestret

  2. French Reference Center on Paraneoplastic Neurological Syndrome, Hospices civils de Lyon, Lyon, France

    Mathilde Small, Géraldine Picard, Véronique Rogemond, Stéphanie Lay, Dimitri Psimaras, Jérôme Honnorat & Virginie Desestret

  3. University of Lyon, Université Claude Bernard Lyon 1, Lyon, France

    Mathilde Small, Coline Couillault, Nathalie Bendriss-Vermare, Christophe Caux, Bertrand Dubois, Jérôme Honnorat & Virginie Desestret

  4. Department of Biopathology, Centre Leon Berard, Lyon, France

    Isabelle Treilleux, Daniel Pissaloux & Sandrine Paindavoine

  5. INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de Recherche en Cancérologie de Lyon, Lyon, France

    Coline Couillault, Nathalie Bendriss-Vermare, Christophe Caux & Bertrand Dubois

  6. Cancer Genomics Platform, Department of Translational Research, Centre Leon Berard, Lyon, France

    Daniel Pissaloux, Sandrine Paindavoine, Valery Attignon & Qing Wang

  7. Department of Oncology, Groupe GINECO, Centre Leon Berard, Lyon, France

    Isabelle Ray-Coquard

  8. Gynecologic Oncology Center, Kiel, Germany

    Jacobus Pfisterer

  9. Centre Francois Baclesse, Groupe GINECO, Caen, France

    Florence Joly

  10. Kliniken Essen Mitte, Essen, Germany

    Andreas Du Bois

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  1. Mathilde Small
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Correspondence to Jérôme Honnorat.

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Patients had died or given their written consent for the use of their tumor and blood samples for research purposes. For genetic analysis, DNA from blood lymphocytes was obtained from NeuroBioTec Hospices Civils de Lyon BRC (France, AC-2013-1867, NFS96-900) with an approval from an independent review board (Comité de Protection des Personnes Sud-Est IV).

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Small, M., Treilleux, I., Couillault, C. et al. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathol 135, 569–579 (2018). https://doi.org/10.1007/s00401-017-1802-y

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