Genetic deficiency of complement isoforms C4A or C4B predicts improved survival of metastatic renal cell carcinoma.
OBJECTIVE
Autoimmune phenomena during immunotherapy are associated with favorable outcomes in patients with metastatic renal cell carcinoma. We have reported improved survival in patients with stage IV renal cell carcinoma who carry 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. A 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. In the current study we tested the hypothesis that C4A or C4B deficiency predicts improved survival of patients with RCC.


METHODS
The 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 restriction fragment length polymorphism.


RESULTS
Genetic complotypes were determined in 61 patients. Individuals with a solitary copy of either C4 isoform experienced longer survival. Median survival from the diagnosis of metastatic disease in patients with a solitary copy of C4A or C4B was 7.75 years vs 1.25 in the comparison group (p = 0.001). This was independent of the benefit derived from autoimmune class II genotypes.


CONCLUSIONS
Improved survival is seen in patients with C4A or C4B deficiency and renal cell carcinoma treated with cytokine therapy with or without surgery. These data support our hypothesis that patients with renal cell carcinoma who have autoimmune genotypes have favorable outcomes resulting from autoimmune mechanisms directed to the tumor.
Zafar
Ghazal I
GI
Department of Experimental Therapeutics and Division of Quantitative Sciences (WW, MMJ), University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Grimm
Elizabeth A
EA
Wei
Wei
W
Johnson
Marcella M
MM
Ellerhorst
Julie A
JA
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality* / Q000556:secondary; D015934:Complement C4a / Q000235:genetics*; D015935:Complement C4b / Q000235:genetics*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms; D015996:Survival Rate
D020033:Protein Isoforms; D015934:Complement C4a; D015935:Complement C4b