Association of anti‐<scp>RNA</scp> polymerase <scp>III</scp> antibody and malignancy in Japanese patients with systemic sclerosis

Saigusa, Ryosuke; Asano, Yoshihide; Nakamura, Kouki; Miura, Shunsuke; Ichimura, Yohei; Takahashi, Takehiro; Toyama, Tetsuo; Taniguchi, Takashi; Noda, Shinichi; Aozasa, Naohiko; Akamata, Kaname; Sumida, Hitoshi; Miyazaki, Makito; Tamaki, Zenshiro; Yanaba, Koichi; Kuwano, Yoshihiro; Sato, Shinichi

doi:10.1111/1346-8138.12827

Cited by 39 publications

(38 citation statements)

References 17 publications

(26 reference statements)

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“…The existence of antibodies against the RNA polymerases has been recognized for many years in scleroderma patients . The recent observation that autoantibodies to RPC155 in scleroderma define a group of patients with a higher risk of cancer (standardized incidence ratio 2.84 [95% confidence interval 1.89–4.10]; odds ratio ranging from 3.85 to 5.83) occurring within a short interval of scleroderma onset has been confirmed in multiple different cohorts . Mechanistic studies in scleroderma patients with cancer have demonstrated that somatic mutations at the POLR3A locus are present in the cancers of some anti‐RPC155–positive patients, in whom mutation‐specific and cross‐reactive T cell immune responses develop .…”

Section: Discussionmentioning

confidence: 98%

“…This relationship between cancer and scleroderma emergence has been most notable among scleroderma patients with antibodies against the large subunit of RNA polymerase III (RPC155). Scleroderma patients with these autoantibodies have a significantly higher risk of developing cancer within a short interval of scleroderma onset compared to scleroderma patients without anti‐RPC155 antibodies . Furthermore, recent data demonstrate that this translates to a 2.8‐fold increased risk of cancer within 3 years of scleroderma onset when compared to the expected cancer incidence in the general population .…”

Section: Introductionmentioning

confidence: 99%

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

Shah

Laiho

Rosen

et al. 2019

Arthritis & Rheumatology

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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.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Shah

Laiho

Rosen

et al. 2019

Arthritis & Rheumatology

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“…A novel property of anti‐RNAP III antibody is the high frequency of malignancy development synchronous with SSc onset . Importantly, the mutation of the POLR3A gene in concomitant tumor cells is detectable in most, but not all, of anti‐RNAP III antibody‐positive patients synchronously diagnosed as having SSc and malignancy, indicating that a certain subset of SSc patients with this antibody may be induced by autoimmune reaction to mutated RNAP III proteins.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the high titer of this antibody is a risk factor for scleroderma renal crisis (SRC) . Also, the high prevalence of synchronous malignancy has been reported in SSc patients with this antibody irrespective of ethnicities . On the other hand, we recently experienced two consecutive SSc patients with this antibody who underwent SBI.…”

Section: Introductionmentioning

confidence: 99%

“…9 Also, the high prevalence of synchronous malignancy has been reported in SSc patients with this antibody irrespective of ethnicities. 10 On the other hand, we recently experienced two consecutive SSc patients with this antibody who underwent SBI. Given that the measurement of anti-RNAP III antibody had been commercially unavailable until a half-decade ago, it is assumed that the association of this antibody with SBI-related SSc has remained uncovered.…”

Section: Introductionmentioning

confidence: 99%

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Association of anti‐RNA polymerase III antibody and silicone breast implants in patients with systemic sclerosis

Saigusa

Asano

Nakamura

et al. 2016

The Journal of Dermatology

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Systemic sclerosis (SSc) is believed to be caused by a complex interplay between genetic factors and environmental influences. Although silicone has been considered to be a candidate of environmental agents, clinical data presented so far fail to show a significant association between silicone breast implant (SBI) and the development of SSc. Because we recently experienced two consecutive SSc patients with anti-RNA polymerase III (RNAP III) antibody who underwent SBI, we here investigated the association of SBI history with the development of SSc positive for anti-RNAP III antibody. Among 262 Japanese SSc patients, of note, the frequency of SBI history was significantly higher in the anti-RNAP III antibody group (16.0% [4/25]) than in the anti-topoisomerase I antibody group (0% [0/87], P < 0.005) and in the anticentromere antibody group (1.2% [2/150], P < 0.005). These results suggest that SBI could influence the development of SSc in a certain subset of patients with anti-RNAP III antibody.

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Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course

Kim,

Woods,

Gutierrez‐Alamillo

et al. 2023

Arthritis & Rheumatology

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ObjectivesWe examined whether an array of scleroderma autoantibodies associates with risk of cancer and could be useful tools for risk stratification.MethodsScleroderma cancer cases and scleroderma controls without cancer from Johns Hopkins and University of Pittsburgh Scleroderma Centers were studied. Sera were assayed by Lineblot and ELISA for autoantibodies against centromere, topoisomerase 1, RNA polymerase III (POLR3), PM/Scl, Th/To, NOR90, U3RNP, Ku, Ro52, U1RNP, and RNPC3. Logistic regression models were constructed to examine whether distinct autoantibodies associated with overall cancer at any time and cancer‐associated scleroderma (cancer occurring ±3 years of scleroderma onset). The effects of having >1 autoantibody on cancer were further examined using random forest analysis.Results676 cases and 687 controls were studied. After adjusting for relevant covariates, anti‐POLR3 (OR 1.47, 95%CI 1.03‐2.11) and monospecific anti‐Ro52 (OR 2.19, 95%CI 1.29‐3.74) associated with an increased overall cancer risk, whereas anti‐centromere (OR 0.69, 95%CI 0.51‐0.93) and anti‐U1RNP (OR 0.63, 95%CI 0.43‐0.93) associated with lower risk. When examining risk of cancer‐associated scleroderma, these immune responses remained associated with increased or decreased risk: anti‐POLR3 (OR 2.28, 95%CI 1.33‐3.91), monospecific anti‐Ro52 (OR 2.58, 95%CI 1.05‐6.30), anti‐centromere (OR 0.39, 95%CI 0.20‐0.74), and anti‐U1RNP (OR 0.32, 95%CI 0.11‐0.93). Anti‐Ro52 plus anti‐U1RNP or anti‐Th/To was associated with decreased cancer risk compared to anti‐Ro52 alone.ConclusionsThese data suggest that 5 distinct scleroderma immune responses, alone or in combination, may be useful tools to stratify scleroderma patients’ cancer risk. Further study examining cancer risk in autoantibody subgroups relative to the general population is warranted.image

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Association of anti‐RNA polymerase III antibody and malignancy in Japanese patients with systemic sclerosis

Cited by 39 publications

References 17 publications

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

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

Association of anti‐RNA polymerase III antibody and silicone breast implants in patients with systemic sclerosis

Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course

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