Circulating Tumor DNA in Patients with Early-Onset Systemic Sclerosis and Dermatomyositis
Background: Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune diseases that have been proposed as models of cancer immunoediting. Autoantibody-defined subsets show divergent cancer risks, yet malignancy often remains clinically occult. We tested whether circulating tumor DNA (ctDNA) can reveal subclinical cancer in new-onset SSc and DM. Methods: We prospectively recruited adults with recent SSc or DM onset. Plasma ctDNA was assessed using a targeted next-generation sequencing panel covering commonly mutated cancer genes. Patients were followed for 18-24 months on average. ctDNA positivity was correlated with subsequent cancer diagnoses. Findings: Among 134 patients (69 SSc, 65 DM), cancer was diagnosed in six (4.5%; three SSc, three DM). ctDNA was detected in four of these six patients (67%) a median of 13 months (range 1.4-17) before clinical diagnosis; in three of four patients, mutations detected in plasma matched those subsequently identified in the same patients primary tumors. ctDNA was also detected in 16 of 128 patients without a cancer diagnosis. ctDNA positivity conferred an 11.4-fold higher risk of malignancy relative to ctDNA negativity and yielded a negative predictive value of 98% and a positive predictive value of 20% for cancer within the observation window. Interpretation: ctDNA testing identified most cancers that emerged within 18 months in new-onset SSc and DM and stratified near-term cancer risk. These findings support larger, interventional trials to determine whether ctDNA-guided surveillance improves timeliness of cancer detection, optimizes imaging and biopsy strategies, and enhances outcomes in patients with SSc and DM.
Authors
- Ami A. Shah (ORCID: https://orcid.org/0000-0002-1139-2009)
- Christopher A. Mecoli (ORCID: https://orcid.org/0000-0002-1429-8392)
- Livia A Casciola-Rosen (ORCID: https://orcid.org/0000-0002-4172-1539)
- Antony Rosen (ORCID: https://orcid.org/0000-0002-8374-4763)
- Laura Kathleen Hummers (ORCID: https://orcid.org/0000-0002-4864-4011)
- Lisa Dobbyn (ORCID: https://orcid.org/0000-0002-3159-189X)
- Natalie Silliman (ORCID: https://orcid.org/0000-0002-5198-9037)
- Matthew Beauregard Smith (ORCID: https://orcid.org/0000-0002-3145-1782)
- Christopher Blair Douville (ORCID: https://orcid.org/0000-0002-2510-4151)
- Janine Ptak (ORCID: https://orcid.org/0000-0003-1934-8739)
- Nickolas Papadopoulos (ORCID: https://orcid.org/0000-0001-7135-7451)
- Adrianne Woods
- Maria Popoli (ORCID: https://orcid.org/0000-0003-2151-7749)
- Kenneth W. Kinzler (ORCID: https://orcid.org/0000-0001-5591-1176)
- Julie J. Paik (ORCID: https://orcid.org/0000-0001-8436-1601)
- Fredrick M. Wigley (ORCID: https://orcid.org/0000-0003-0762-6981)
- Chetan Bettegowda (ORCID: https://orcid.org/0000-0001-9991-7123)
- Lisa Christopher‐Stine (ORCID: https://orcid.org/0000-0002-7150-7306)
- Gwen Leatherman
- Bert Vogelstein (ORCID: https://orcid.org/0000-0003-0766-3854)
- Jemima Albayda (ORCID: https://orcid.org/0000-0002-8030-9504)
- Yuxuan Wang (ORCID: https://orcid.org/0000-0002-2932-6042)
- Ji Soo Kim (ORCID: https://orcid.org/0009-0003-5755-4426)
- XingYao Wang
- Sam D Curtis
- Lauren Fisher
Institutions
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
Publication Details
- Journal
- medRxiv
- Published
- 2026-11-06
- DOI
- https://doi.org/10.64898/2026.11.06.26364657
- Primary Topic
- Systemic Sclerosis and Related Diseases
- Type
- preprint
Funders
- Lustgarten Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- Jerome L. Greene Foundation
- National Institutes of Health
- Donald B. and Dorothy L. Stabler Foundation