Specific genetic alterations and tumor immune contexture characterize ovarian tumors with paraneoplastic degeneration and anti-Yo antibodies

Background Paraneoplastic cerebellar degeneration with anti-Yo antibodies (Yo-PCD) are rare autoimmune neurological diseases triggered by ovary or breast cancers. However, mechanisms allowing breakdown of immune tolerance to tumor antigens (Ags) are still unclear. Methods We collected 25 samples of Yo-PCD ovarian cancers to analyze the immunohistological (IHC) characteristics of these tumors and to perform genomic study by aCGH and NGS. We compared the results to 116 ovarian tumors without Yo-PCD. Results Yo-PCD ovarian tumors strikingly differ from those of non-PCD patients. Although 23 out of 25 are histologically classical high-grade serous carcinoma, they are characterized by increased immune cell infiltration, organization of T and B cells in tertiary lymphoid structures and presence of mature DC in contact with tumor cells. Analyzing the genes encoding for the Yo Ags, e.g. CDR2 and CDR2L, CGH revealed significant recurrent gains in CDR2L gene copy numbers in Yo-PCD tumors. CDR2L overexpression was detected by IHC in all Yo-PCD ovarian cancers. Moreover, NGS analysis revealed that 65% of the Yo-PCD ovarian cancer presented missense or non-sense mutations in at least 1 of the Yo Ags, while only 0.1% of un-selected ovarian tumors were mutated. No constitutional mutations were detected in Yo-PCD patients. Finally, all but 2 Yo-PCD ovarian cancers carried at least one genetic alteration on CDR2 or CDR2L genes (gains and/or mutations). Conclusions Altogether, these data show that genetic alteration of onconeural Ags, including gains and mutations, might be instrumental for induction of the remarkable anti-tumor immune response characterizing PCD.