Purpose-Autoimmune phenomena during immunotherapy are associated with favorable outcomes for patients with metastatic renal cell carcinoma (RCC). We have reported improved survival for Stage IV RCC patients carrying autoimmunity-associated HLA class II haplotypes. We propose that the clinical benefit is mediated by products of other autoimmunity-associated genes linked to these haplotypes. One candidate gene is complement C4, which replicates as part of the RCCX module, can be present in multiple copies, and exists as C4A and C4B isoforms. Deficiencies of either isoform are associated with autoimmunity. The objective of this study was to test the hypothesis that C4A or C4B deficiency predicts improved survival for patients with RCC.Materials and Methods-Total C4 copy number was determined by simultaneous amplification of RP1 and TNXA/RP2 to quantitate RCCX modules. C4A and C4B alleles were distinguished by PshAI RFLP.Results-Genetic complotypes were determined for 61 patients. Individuals with a solitary copy of either C4 isoform experienced longer survival. The median survival from the diagnosis of metastatic disease for patients with a solitary copy of C4A or C4B was 7.75 years vs. 1.25 years for the comparison group (p = 0.001), and was independent of the benefit derived from autoimmune class II genotypes.Conclusions-We conclude that improved survival is seen for RCC patients with C4A or C4B deficiency, treated with cytokine therapy with/without surgery. These data support our hypothesis that RCC patients with autoimmune genotypes have favorable outcomes resulting from autoimmune mechanisms directed to the tumor.
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