Protective Effect Against Cancer of Antibodies to the Large Subunits of Both RNA Polymerases I and III in Scleroderma

Objective: While compelling data suggest a cancer-induced autoimmunity model in scleroderma patients with anti–RNA polymerase III large subunit (anti-RPC155) antibodies, ~85% of these patients do not manifest cancer. This study was undertaken to determine whether additional autoantigens are targeted in anti-RPC155–positive scleroderma patients without detectable cancer. Methods: The study included 168 scleroderma patients with anti-RPC155 antibodies (80 with a history of cancer and 88 with no cancer diagnosis after >5 years of follow-up). Thirty-five sera (17 from patients with cancer and 18 from patients without cancer) were randomly selected for autoantibody discovery using immunoprecipitation (IP). An ~194-kd band was enriched in the subgroup without cancer; this was identified as RNA polymerase I large subunit (RPA194). Results: RPA194 generated by in vitro transcription/translation was used for IPs performed on the entire cohort to test whether anti-RPA194 was enriched among anti-RPC155–positive patients without cancer. Anti-RPA194 antibodies were significantly more common in the group without cancer (16 [18.2%] of 88) than in the group with cancer (3 [3.8%] of 80) (P = 0.003). Patients with both anti-RPA194 and anti-RPC155 were significantly less likely to have severe gastrointestinal disease than patients with anti-RPC155 only (26.3% versus 51.0%; P = 0.043). Conclusion: Anti-RPA194 antibodies are enriched in anti-RPC155–positive scleroderma patients without cancer. Since somatic mutations in the gene encoding RPC155 in cancer in scleroderma patients appears to play a role in immune response initiation against RPC155 in those patients, these data raise the possibility that the development of immune responses to both RPC155 and RPA194 may influence clinical cancer emergence. Further study is required to define whether different autoantibody combinations have utility as tools for cancer risk stratification in scleroderma.