# Autoantibodies Define Scleroderma Subgroups with Distinct Relationships to Cancer

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $616,811

## Abstract

PROJECT SUMMARY
Although an understanding of the biological mechanisms causing scleroderma (SSc) remains incomplete,
emerging data underscore important connections linking cancer, autoimmunity and SSc. It is an important
priority to identify SSc subgroups at high risk of cancer at SSc onset, as this may inform therapeutic
approaches and provide insights into SSc pathogenesis. Our recent studies show that autoantibodies are
useful to define biologically relevant subgroups. Among SSc patients with cancer, those with anti-RNA
polymerase III (POLR3) antibodies are more likely to have cancer close to SSc onset (3, 4). However, >25% of
patients with a short cancer-SSc interval currently have undefined autoantibodies. We have created an
innovative autoantibody discovery pipeline, and demonstrate that multiple, additional autoantibodies (known and
novel) are associated with coincident cancer at SSc onset. We also describe a novel antibody specificity that is
enriched in anti-POLR3-positive patients who do not get cancer, suggesting that some immune responses might
be protective against cancer. Lastly, we demonstrate that autoantibody subsets can aid in defining the magnitude
and timing of cancer risk in SSc, and in predicting the types of tumors observed. The proposed studies will use
a large population of SSc patients from two well-characterized SSc cohorts to define and validate autoantibodies
associated with increased or decreased cancer risk, and to assess their utility, together with distinct phenotypic
features, in quantifying cancer risk at SSc onset. We will accomplish this through the following specific aims:
Aim 1 will use an innovative antibody discovery pipeline and a rich cohort of SSc patients with cancer to identify
known and novel autoantibody markers of a short cancer-SSc interval in patients lacking the 3 major SSc
antibody specificities. The studies will also use the defined autoantibodies to search for evidence of somatic
mutations of relevant autoantigens in matched cancers. Since ~80% of patients with POLR3 antibodies do not
have cancer, and our preliminary data shows novel antibodies in this group, we will also identify autoantibodies
associated with protection against cancer. These may be important markers of low cancer risk. Aim 2 will define
time-dependent overall and site-specific cancer risk in patients with SSc relative to the general population, based
on autoantibody and phenotypic subsets, to develop an evidence-based approach to cancer screening in
patients with new onset SSc. Findings will be validated in a second large SSc cohort. This work will allow the
development of a clinically relevant approach to cancer detection at SSc onset and establish a
framework of more homogeneous serologic subgroups in whom the mechanistic relationships between
cancer and autoimmunity can be interrogated. This approach is also relevant to other autoimmune
rheumatic diseases (e.g. inflammatory myopathies) in which cancer and rheumatic disea...

## Key facts

- **NIH application ID:** 10132986
- **Project number:** 5R01AR073208-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** LIVIA A CASCIOLA-ROSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $616,811
- **Award type:** 5
- **Project period:** 2018-04-09 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132986

## Citation

> US National Institutes of Health, RePORTER application 10132986, Autoantibodies Define Scleroderma Subgroups with Distinct Relationships to Cancer (5R01AR073208-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132986. Licensed CC0.

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