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SP0017 Shared mechanisms in cancer and autoimmunity
  1. A Rosen
  1. Medicine/Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Md 21205, United States

Abstract

Some rheumatic disease autoantibodies are powerful markers of subgroups of patients who have distinct disease phenotypes and trajectories. Of particular interest are markers of several disease subgroups in whom cancer and rheumatic disease onset are clustered together in time. For example, a subgroup of scleroderma patients have coincident onset of cancer and scleroderma. This is observed in scleroderma patients with autoantibodies against the RNA polymerase-3 (POLR3), and more recently with autoantibodies recognizing the minor spliceosome. In autoimmune myopathies, temporal clustering of diagnosis of cancer and myositis is associated with autoantibodies to NXP2 and components of the TIF1 complex. Interestingly, although the incidence of cancer is higher in patients with these autoantibodies, most patients with these autoantibodies manifest cancer, even with extended periods of follow-up. These observations provide an important opportunity to investigate the potential mechanisms which operate at the cancer-immune interface during development of rheumatic diseases.

We have investigated such mechanisms in scleroderma patients with autoantibodies to POLR3 who also had a cancer diagnosed an average of -2.6 years from scleroderma onset. In cancers from these patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to POLR3 but not in eight patients without these antibodies. 3 antibody-positive patients had somatic mutations in POLR3A; 5 patients had loss of heterozygosity at the POLR3A locus. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations sparked cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma, and potentially other autoimmune syndromes. They suggest that somatic mutations in autoantigens in different cancers might initiate an immune response to the mutated autoantigen, which spreads to include the wild type version. Tissues (e.g. blood vessels, regenerating muscle) in which specific autoantigens are expressed at high levels, or potentially play critical functional roles, may be particularly susceptible to immune-mediated dysfunction. The results also provide support for the idea that acquired immunity helps to control naturally occurring cancers in patients with autoimmune rheumatic diseases; it is possible that this immune response may sometimes be fully effective, preventing the emergence of cancer.

Disclosure of Interest None declared

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