Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo-Associated Paraneoplastic Cerebellar Degeneration.

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.

Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies.

BACKGROUND: Paraneoplastic neurological syndromes are rare conditions where an autoimmune reaction against the nervous system appears in patients suffering from a tumour, but not linked to the spreading of the tumour. A break in the immune tolerance is thought to be the trigger. METHODS: The transcriptomic profile of 12 ovarian tumours (OT) from patients suffering from paraneoplastic cerebellar degeneration (PCD) linked to anti-Yo antibodies (anti-Yo PCD OT) was compared with 733 ovarian tumours (OT control) from different public databases using linear model analysis. RESULTS: A prominent significant transcriptomic over-representation of CD8+ and Treg cells was found in anti-Yo PCD OT, as compared to the OT control. However, the overall degree of immune cell infiltration was similar, according to the ESTIMATE immune score. We also found an under-representation of M2 macrophages in anti-Yo PCD OT. Furthermore, the differentially expressed genes were enriched for AIRE-related genes, a well-known transcription factor associated with a broad range of autoimmune diseases. Finally, we found that the differentially expressed genes were correlated to the transcriptomic profiling of the cerebellar structures. CONCLUSIONS: Our data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.

Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration.

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.

Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies.

Anti-Yo paraneoplastic cerebellar degeneration (PCD) is a devastating autoimmune complication of gynecological cancers. We hypothesized that as for other autoimmune diseases, specific HLA haplotypes are associated. We conducted high resolution HLA typing of Class I/Class II in 40 cases versus ethnically matched controls. Three cases with anti-Yo antibodies and peripheral neuropathy were also included. We detected protective effects of DPA1*01:03~DPB1*04:01 (OR=0, p=0.0008), DRB1*04:01~DQA1*03:03(OR=0, p=0.0016) and DPA1*01:03~DPB1*04:01 (OR=0.35, p=0.0047) overall. Increased DRB1*13:01~DQA1*01:03~DQB1*06:03 was also found in PCD ovarian cases (OR=5.4, p=0.0016). These results suggest differential genetic susceptibility to anti-Yo per cancer and with a primary HLA Class II involvement.

Human epidermal growth factor receptor 2 overexpression in breast cancer of patients with anti-Yo--associated paraneoplastic cerebellar degeneration.

Isolated case reports suggest that breast tumors from patients with paraneoplastic cerebellar degeneration (PCD) and Yo antibodies overexpress human epidermal growth factor receptor 2 (HER2). HER2 overexpression is present in 15%-25% of breast cancers and is associated with poor prognosis. We retrospectively analyzed the status of HER2 in breast tumors of 27 patients with anti-Yo-associated PCD to evaluate whether HER2 overexpression in this group of patients is higher than expected. In addition, we analyzed HER2 status of 19 breast tumors from patients with paraneoplastic neurological syndromes and Ri antibodies to see whether HER2 was specifically related to anti-Yo-associated PCD. We also assessed cdr2 expression (the onconeural antigen recognized by Yo antibodies) in 21 HER2-positive breast tumors from patients without paraneoplastic neurological syndromes. HER2 was overexpressed in 26 patients (96.3%) with anti-Yo-associated PCD but only in 2 patients (10.5%) with paraneoplastic neurological syndromes associated with Ri antibodies (P< .0001). Only 5 (23.8%) of the 21 HER2-positive breast tumors showed cdr2 immunoreactivity. This study shows a very high frequency of HER2 overexpression in breast cancers in patients with anti-Yo-associated PCD but not in those from patients with Ri antibodies. Although the expression of cdr2 onconeural antigen is not high in HER2-positive breast cancers, HER2 overexpression seems to be an important requirement to develop an anti-Yo-associated PCD.

Carbonic anhydrase-related protein VIII: autoantigen in paraneoplastic cerebellar degeneration.

Serum of a patient with paraneoplastic cerebellar degeneration (PCD) and malignant melanoma had a unique reactivity with Purkinje cells that was not observed in serum of patients with PCD and other tumors, or with malignant melanoma without paraneoplastic syndromes. The screening of a human cerebellar complementary DNA expression library with the patient's serum resulted in the isolation of the CA8 gene. CA8 encodes carbonic anhydrase-related protein (CARP) VIII, preferentially expressed in Purkinje cells. The patient had intrathecal synthesis of CARP VIII antibodies. One of seven melanomas tested expressed CARP VIII. These data suggest CARP VIII may be an autoantigen involved in the pathogenesis of melanoma-associated PCD.