Onconeuronal antigen Cdr2 correlates with HIF prolyl-4-hydroxylase PHD1 and worse prognosis in renal cell carcinoma

• Cdr2 protein expression in pRCC patients correlates with PHD1 protein expression.
• Strong Cdr2 expression is associated with decreased survival of ccRCC patients.
• Cdr2 expression in cancer does not necessarily lead to the development of PCD.

Neoplastic expression of the onconeuronal cerebellar degeneration-related antigen Cdr2 in ovary and breast tumors is associated with paraneoplastic cerebellar degeneration (PCD). Cdr2 protein expression is normally restricted to neurons, but aberrant Cdr2 expression has mainly been described for breast and ovarian tumors. Previously, we found strong Cdr2 protein expression in the papillary subtype of renal cell carcinoma (pRCC) and showed that Cdr2 interacts with the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1. High Cdr2 protein levels are associated with decreased HIF-dependent gene expression in cells as well as in clinical pRCC samples, providing a possible explanation why pRCCs are the most hypovascular renal tumors. Here, we demonstrate that strong Cdr2 protein expression in clinical samples from pRCC patients correlates with elevated PHD1 protein levels, suggesting that increased PHD1 activity attenuates HIF-dependent gene expression. Interestingly, survival analysis revealed a significant correlation between high levels of Cdr2 expression and worse patient outcome in clear cell (cc) RCC patients. These findings provide evidence that Cdr2 might represent an important tumor antigen in kidney cancer and possibly in other cancer types as well. In contrast to ovary and breast tumor patients who develop PCD, no Cdr2 auto-antibodies were detected in the serum of pRCC patients, which is in line with the fact that pRCC patients have not been reported to display paraneoplastic neurodegenerative syndromes. This suggests that, despite a shared target antigen, tumor immunity and autoimmunity only partially overlap, and also highlights to which extent immuno-surveillance against cancer can be clinically silent.