PT - JOURNAL ARTICLE AU - Peter, Elise AU - Treilleux, Isabelle AU - Wucher, Valentin AU - Jougla, Emma AU - Vogrig, Alberto AU - Pissaloux, Daniel AU - Paindavoine, Sandrine AU - Berthet, Justine AU - Picard, Géraldine AU - Rogemond, Véronique AU - Villard, Marine AU - Vincent, Clémentine AU - Tonon, Laurie AU - Viari, Alain AU - Honnorat, Jérôme AU - Dubois, Bertrand AU - Desestret, Virginie TI - Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo–Associated Paraneoplastic Cerebellar Degeneration AID - 10.1212/NXI.0000000000200015 DP - 2022 Sep 01 TA - Neurology - Neuroimmunology Neuroinflammation PG - e200015 VI - 9 IP - 5 4099 - http://nn.neurology.org/content/9/5/e200015.short 4100 - http://nn.neurology.org/content/9/5/e200015.full SO - Neurol Neuroimmunol Neuroinflamm2022 Sep 01; 9 AB - Background and Objectives Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors' genetic and immune specificities involved in Yo-PCD pathogenesis.Methods Using clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs.Results Yo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G–plasma cells.Discussion These data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.BC=breast cancer; CDR2=cerebellar degeneration-related protein 2; CGHa=comparative genomic hybridization array; CNV=copy number variation; COSMIC=Catalogue Of Somatic Mutations In Cancer; DCIS=ductal carcinoma in situ; ECM=extracellular matrix; FFPE=formalin-fixed paraffin-embedded; GO=Gene Ontology; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; IF=immunofluorescence; IgG=immunoglobulin G; IHC=immunohistochemistry; MCP=Microenvironment Cell Populations; mDC=myeloid dendritic cell; NST=no special type; OBC=occult BC; OR=estrogen receptor; PCD=paraneoplastic cerebellar degeneration; PR=progesterone receptor