Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies

Abstract

Objective. This study was undertaken to examine the temporal relationship between scleroderma development and malignancy, and to evaluate whether this differs by autoantibody status among affected patients.Methods. Study participants had a diagnosis of scleroderma, a diagnosis of cancer, cancer, an available serum sample, and a cancer pathology specimen. Sera were tested for autoantibodies against topoisomerase I, centromere, and RNA polymerase I/III by immunoprecipitation and/or enzyme-linked immunosorbent assay. Clinical and demographic characteristics were compared across autoantibody categories. Expression of RNA polymerases I and III was evaluated by immunohistochemistry using cancerous tissue from patients with anti-RNA polymerase antibodies.Results. Twenty-three patients were enrolled. Six patients tested positive for anti-RNA polymerase I/III, 5 for anti-topoisomerase I, and 8 for anticentromere, and 4 were not positive for any of these antigens. The median duration of scleroderma at cancer diagnosis differed significantly between groups (؊1.2 years in the anti-RNA polymerase I/III group, ؉13.4 years in the antitopoisomerase I group, ؉11.1 years in the anticentromere group, and ؉2.3 years in the group that was negative for all antigens tested) (P ‫؍‬ 0.027). RNA polymerase III demonstrated a robust nucleolar staining pattern in 4 of 5 available tumors from patients with antibodies to RNA polymerase I/III. In contrast, nucleolar RNA polymerase III staining was not detected in any of 4 examined tumors from the RNA polymerase antibody-negative group (P ‫؍‬ 0.048).Conclusion. Our findings indicate that there is a close temporal relationship between the onset of cancer and scleroderma in patients with antibodies to RNA polymerase I/III, which is distinct from scleroderma patients with other autoantibody specificities. In this study, autoantibody response and tumor antigen expression are associated. We propose that malignancy may initiate the scleroderma-specific immune response and drive disease in a subset of scleroderma patients.

Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer

“…The recent observation that scleroderma and cancer can present synchronously, particularly in patients with autoantibodies to POLR3 (6,7), prompted studies to define whether cancer and scleroderma might be mechanistically related in this subgroup of patients. Somatic mutation and loss of heterozygosity (LOH) within the gene (POLR3A) encoding the 155-kDa large subunit of RNA polymerase III occur frequently in cancers from patients with scleroderma with anti-POLR3 autoantibodies (8).…”

Incidence and the Risk Factor of Malignancy in Japanese Patients with Systemic Sclerosis

“…It is controversial whether smoking is a risk factor for lung cancer in SSc patients (34,44), and should be ascertained. Recent reports indicated the relation between malignancy and anti-RNA polymerase III antibody (45,46), which is a characteristic autoantibody in SSc patients. In addition to the limitations of this study derived from the sample size, regional/racial characteristics, or analyzed clinical factors, it should be mentioned that this is a retrospective cohort study in which not every patient took a series of examinations including autoantibody tests or imaging methods to detect each organ involvement or malignancy.…”

The role of the acquired immune response in systemic sclerosis

“…In fact, in many cases, the detection of autoreactive T cells has shown poor specificity as they were found also in anti-topo-1-negative patients as well as healthy controls [58, 81,88,112]. More recently, a close temporal association between the onset of SSc and the detection of cancer has been described in a subset of patients positive for anti-RNA polymerase III antibodies [101]. This observation has lead to the discovery that mutated autoantigens (RNApol3) are present in the tumors obtained from these patients and result in mutant-specific T cell immune responses as well as in the generation cross-reactive autoantibodies [46].…”