Vascular and mesenchymal signatures of breast cancers associated with Yo and Ri paraneoplastic syndrome.

Paraneoplastic neurological syndromes (PNSs) are rare autoimmune diseases that occur in the context of cancer, but the mechanisms leading to immune tolerance breakdown remain unknown. Breast cancers (BCs) associated with Yo-PNS and Ri-PNS show distinct immune and genetic specificities, suggesting that tumour characteristics may contribute to autoimmunity. Herein, we aimed to investigate whether PNS-associated BCs display additional specificities, including stromal and vascular features that have not been systematically assessed. We compared 12 BCs associated with Yo-PNS (Yo-BCs) and 10 BCs associated with Ri-PNS (Ri-BCs) with two independent cohorts of non-PNS breast cancer controls (CtrlYo and CtrlRi) using tumour transcriptomic profiling with a targeted 760-gene panel and complementary immunohistochemistry. Transcriptomic analysis identified 27 genes commonly differentially expressed in Yo-BCs and Ri-BCs compared with their respective controls, including upregulation of FLT4. Immunohistochemistry confirmed increased podoplanin-positive lymphatic structures in both Yo-BCs and Ri-BCs. In parallel, Yo-BCs showed predominant mesenchymal phenotype and downregulation of genes associated with hypoxia (HIF1A, FLT1, LDHA, P4HA2) compared with CtrlYo. These features were not present in Ri-BCs when compared with CtrlRi. These findings not only highlight subtype-specificities of Yo- and Ri-associated BCs, but also identify lymphangiogenesis as a shared tumour-intrinsic feature that may be part of a cancer-specific context required to initiate or sustain autoimmunity in PNS.