The renal cell carcinoma is the ninth most common cancer with an increasing occurrence and mortality. Recoverin is the first retina-specific photoreceptor protein that was shown to undergo aberrant expression, due to its promoter demethylation, as a cancer-retina antigen in a number of malignant tumors. In this work, we demonstrated that recoverin is indeed expressed in 68.4 % of patients with different subtypes of renal cell carcinoma, and this expression has tendency to correlate with tumor size. Interestingly, 91.7 % of patients with the benign renal tumor, oncocytoma, express recoverin as well in their tumor. Epigenetic analysis of the recoverin gene promoter revealed a stable mosaic methylation pattern with the predominance of the methylated state, with the exception of -80 and 56 CpG dinucleotides (CpGs). While the recoverin expression does not correlate withoverall survival of the tumor patients, the methylation of the recoverin gene promoter at -80 position is associated with better overall survival of the patients. This work is the first report pointing towards the association of overall survival of renal cell carcinoma (RCC) patients with promoter methylation of a cancer-retina antigen. Taken together, these data allow to consider recoverin as a potential therapeutic target and/or marker for renal tumors.

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Abstract. In cancer, the retinal Ca 2+ -binding protein recoverin is a paraneoplastic antigen, the aberrant expression of which is capable of triggering the appearance of specific autoantibodies in the serum of patients with malignant tumors and the subsequent development of a paraneoplastic syndrome, cancer-associated retinopathy (CAR). The frequency of serum autoantibodies against recoverin (AAR), earlier determined at a rate of 15-20% in lung cancer, is much higher than the frequency of CAR syndrome, which is approximately 1%. In the present study, we estimated for the first time the frequencies of serum AAR in patients with various types of malignancies other than lung cancer. Patient biospecimens were collected to analyze for the presence of AAR. Additionally, various cell lines were cultivated and analyses were performed using Western blotting and RT-PCR. Results showed that in all cases tested, the AAR frequencies did not exceed 10%. Five AAR-positive patients with various types of cancer were available for ophthalmological investigation and only one of these patients had CAR syndrome. This result is consistent with the conclusion made in our previous studies of lung cancer that serum AAR do not necessarily trigger the development of CAR syndrome. IntroductionNeuronal proteins, which are usually present only within the nervous system but may also be expressed in malignant tumors localized outside the nervous system, are assigned to paraneoplastic (onconeural) antigens (PNA). The immune system of certain patients responds to PNA by producing specific autoantibodies and/or cytotoxic T-cells that trigger the development of a paraneoplastic neurological syndrome (PNS) (1). One such PNA is the photoreceptor Ca 2+ -binding protein recoverin (2,3), which is normally specific to the retina and the pineal gland but may also be aberrantly expressed in malignant tumors of the lung and other tissues (4,5). In certain patients with lung cancer, high-titer serum autoantibodies against recoverin (AAR) trigger the development of a PNS, cancer-associated retinopathy (CAR) (6,7). However, low-titer serum AAR of patients with lung cancer do not necessarily cause CAR syndrome (8-10). Instead, this syndrome only occurs in approximately 1% of cancer patients, whereas the frequencies of serum AAR in patients with small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) equal 15 and 20%, respectively (10).By analogy with cancer-testis antigens, recoverin has been classified as a cancer-retina antigen (5) for the following reasons: i) its normal expression is restricted to an immunoprivileged tissue (retina), ii) it is aberrantly expressed in tumor cells, iii) it subsequently demonstrates high antigenicity (autoantibodies and/or T-cells), and iv) aberrant demethylation of the gene promoter is involved in the aberrant expression of recoverin (11).In this study, we analyzed serial specimens of blood sera of patients with a number of different malignancies to estimate the frequency of serum AAR in oncological disea...