RT Journal Article
SR Electronic
T1 Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo–Associated Paraneoplastic Cerebellar Degeneration
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200015
DO 10.1212/NXI.0000000000200015
VO 9
IS 5
A1 Peter, Elise
A1 Treilleux, Isabelle
A1 Wucher, Valentin
A1 Jougla, Emma
A1 Vogrig, Alberto
A1 Pissaloux, Daniel
A1 Paindavoine, Sandrine
A1 Berthet, Justine
A1 Picard, Géraldine
A1 Rogemond, Véronique
A1 Villard, Marine
A1 Vincent, Clémentine
A1 Tonon, Laurie
A1 Viari, Alain
A1 Honnorat, Jérôme
A1 Dubois, Bertrand
A1 Desestret, Virginie
YR 2022
UL http://nn.neurology.org/content/9/5/e200015.abstract
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