Abstract
BACKGROUNDThe temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). Nevertheless, many patients with anti–TIF1-γ antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti–TIF1-γ–positive patients without cancer.METHODSUsing a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti–TIF1-γ–positive DM patients without cancer. These were subsequently examined in discovery (n = 110) and validation (n = 142) cohorts of DM patients with anti–TIF1-γ autoantibodies.RESULTSWe identified 10 potentially novel autoantibodies in anti–TIF1-γ–positive DM patients, 6 with frequencies ranging from 3% to 32% in 2 independent DM cohorts. Autoantibodies recognizing cell division cycle and apoptosis regulator protein 1 (CCAR1) were the most frequent, and were significantly negatively associated with contemporaneous cancer (discovery cohort OR 0.27 [95% CI 0.7–1.00], P = 0.050; validation cohort OR 0.13 [95% CI 0.03–0.59], P = 0.008). When cancer did emerge, it occurred significantly later in anti-CCAR1–positive compared with anti-CCAR1–negative patients (median time from DM onset 4.3 vs. 0.85 years, respectively; P = 0.006). Cancers that emerged were more likely to be localized (89% of anti-CCAR1–positive cancers presenting at stage 0 or 1 compared with 42% of patients without anti-CCAR1 antibodies, P = 0.02). As the number of additional autoantibody specificities increased in anti–TIF1-γ–positive DM patients, the frequency of cancer decreased (P < 0.001).CONCLUSIONAs the diversity of immune responses in anti–TIF1-γ DM patients increases, the likelihood of cancer emerging decreases. Our findings have important relevance for cancer risk stratification in DM patients and for understanding natural immune regulation of cancer in humans.TRIAL REGISTRATIONNot applicable.FUNDING SOURCESThe NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.
Highlights
A temporal clustering of cancer and dermatomyositis (DM) in a subgroup of DM patients has been appreciated for decades, with diagnosis of cancers prominent in the –3- to +3-year window around DM onset
Recent studies have demonstrated that CAM is much more likely to occur in association with specific autoantibodies, with a majority of cancers occurring in those patients with autoantibodies recognizing tripartite motif–containing 33 (TRIM33), known as transcriptional intermediary factor 1-γ (TIF1-γ) [4, 5]
In a recent study focused on systemic sclerosis (SSc) patients with autoantibodies against POLR3A in whom cancer does not emerge, we found that patients who had autoantibodies against the large subunit of RNA polymerase I (RPA194) had a much lower incidence of cancer than those with antibodies against POLR3A alone [16]
Summary
In anti-POLR3–positive SSc patients, somatic mutations and loss of heterozygosity (LOH) at the POLR3A locus in the associated cancers were frequent; such genetic changes were not seen in cancers from patients with other immune responses in SSc [14] These somatic mutations appear to drive an immune response to the mutated epitope that spreads to the wild-type antigen [14]. The observation that these somatic mutations are only found in a minority of cells in the tumor, combined with LOH at the POLR3A locus, strongly suggest that this subgroup of SSc represents natural cancer immunoediting [14, 15]. The temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). We investigated whether additional autoantibodies are found in anti–TIF1-γ–positive patients without cancer
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