Genetic Deficiency of Complement Isoforms C4A or C4B Predicts Improved Survival of Metastatic Renal Cell Carcinoma

Abstract

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.

Nicotine‐induced protein expression profiling reveals mutually altered proteins across four human cell lines

“…For example, abundance differences in complement C4-A (C4A, Fig. 5C) have been shown previously to predict survival of patients with metastatic renal cell carcinoma [46] and members of the complement family have been also associated with nicotine exposure [47]. An unrelated protein, calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2, Fig.…”

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

“…6,36,37 The exact relationship between disorder and RCCX is unambiguous when a defective gene is involved; 7,38 most often, however, identification of the real causative factors proves fairly challenging. RCCX disease association studies have mainly focused on C4 GCNs, [39][40][41] but forgetting about the complexity of RCCX variations and the longrange LD characteristics of the MHC hides the danger of overseeing the genuine molecular background. More and more detailed descriptions of the region are thus indispensable for our better understanding of RCCX-related disease associations, the first step on the road leading to the most effective prevention and treatments possible.…”

Isobaric Tag‐Based Protein Profiling of a Nicotine‐Treated Alpha7 Nicotinic Receptor‐Null Human Haploid Cell Line

“…Complement C4-A (C4A, Figure 5E) is another protein that is commonly observed to be up-regulated in nicotine-treated cell cultures. C4-A has been shown previously to predict survival of patients with metastatic renal cell carcinoma [40] . Members of the complement family have been also associated with nicotine exposure [41] .…”