Local genetic correlations between systemic sclerosis and common cancer types

RESEARCH ARTICLE Local genetic correlations between systemic sclerosis and common cancer types Karina Patasova 1,2,3¤*, Weng Ian Che4, Helga Westerlind5, Lina Marcela Diaz-Gallo Marie Holmqvist5,7☯ , 1,6☯ 1 Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden, 2 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom, 3 Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom, 4 Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau SAR, China, 5 Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden, 6 Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden, 7 Medical unit Gastro, Dermatology, Rheumatology, Karolinska University Hospital, Stockholm, Sweden ☯ These authors contributed equally to this work ¤ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom * Abstract OPEN ACCESS Citation: Patasova K, Che WI, Westerlind H, Diaz-Gallo LM, Holmqvist M (2026) Local genetic correlations between systemic sclerosis and common cancer types. PLoS One 21(5): e0350006. https://doi.org/10.1371/journal. pone.0350006 Editor: Elingarami Sauli, Nelson Mandela African Institute of Science and Technology, TANZANIA, UNITED REPUBLIC OF Received: September 26, 2024 Accepted: May 7, 2026 Introduction The incidence of cancer, encompassing all major types, is significantly higher among patients with systemic sclerosis (SSc) compared to the general population. While previous studies have assessed the global genetic relationships between SSc and various cancers and found no evidence of causality or pleiotropy, these methods average effects across the genome and thus ignore potential opposing directional effects at different loci, thereby missing locus-specific associations. To address this gap, we assessed fine-scaled genetic overlap between SSc and commonly associated cancers, namely breast and lung cancers, as well as hematologic malignancies, by applying local genetic correlation analyses. Published: May 27, 2026 Copyright: © 2026 Patasova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data availability statement: All GWAS used in the study analyses were extracted from GWAS catalog and Breast cancer consortium. Statistical analyses code published on Zenodo https://doi.org/10.5281/zenodo.18633624. Methods We assessed the genetic relationship between SSc and cancers that frequently co-occur with SSc: breast cancer and its’ four main molecular subtypes: HER2- enriched-like, luminal A and B-like, and triple-negative breast cancers, as well as lung cancer, lymphocytic leukemia, and non-Hodgkin's lymphoma. Published genomewide association study statistics were obtained from the GWAS catalog and The Breast Cancer Association Consortium, and data were standardized, quality control filtered, and preprocessed. Global and local genetic correlations were evaluated using linkage disequilibrium score regression and Local Analysis of [co]Variant Annotation software. Gene-based cross-trait meta-analysis, colocalization and PLOS One | https://doi.org/10.1371/journal.pone.0350006 May 27, 2026 1 / 18 Funding: The study was funded by Swedish Research Council (grant 2020-02445). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. fine-mapping approaches were used to assess evidence of pleiotropy across regions identified by local genetic correlation analyses. We implemented visualization of the local genetic correlations and functional enrichment analyses of pleiotropic genes from these local correlations. Competing interests: The authors have declared that no competing interests exist. Results We did not detect any significant global genetic correlation between SSc and the analyzed cancer subtypes. However, we identified 23 significant local bivariate correlations; 21 were with different molecular subtypes of breast cancer. However, only the locus shared between SSc and lung cancer showed strong evidence of pleiotropy. Genes within loci shared with lung cancer were involved in cell communication and signaling, extracellular matrix remodelling and skin morphogenesis. Conclusions We report a pleiotropic locus between SSc and lung cancer, illuminating potential pathobiological mechanisms and providing gene candidates for future research. Introduction Systemic sclerosis (SSc) is an immune-mediated disease primarily affecting women. It is characterized by vasculopathy and abnormally high extracellular matrix deposition in skin and other organs, leading to fibrosis [1,2]. Similar to other immune- mediated disorders, patients with SSc are at greater risk of developing cancer compared to the general population. In patients with SSc, cancer remains the leading cause of death unrelated to SSc, accounting for over a third of fatalities [3]. The types of cancer that are more common in SSc than in the general population differ across populations. Still, the risk of lung cancer, breast cancer, and hematological malignancies is consistently reported as elevated in SSc [4]. Additionally, evidence points to an intriguing temporal relationship between the onset of SSc and cancer development. In particular, there seems to be a biphasic incidence of cancer; the first peak of cancer coincides with SSc diagnosis, occurring within five years before or after SSc onset and the second more than ten years later. Interestingly, breast carcinomas tend to develop during the first peak, while gastrointestinal tract cancers predominate at the second peak [5]. The first cancer incidence peak coinciding with SSc diagnosis suggests that some cancer types are part of a paraneoplastic phenomenon, whereby autoimmunity is triggered by a protective antitumor response against malignant cells in a genetically susceptible host [6–8]. Cancer risk also appears to be mediated by SSc-associated autoantibodies, such as anti-RNA polymerase III (anti-POL3) and anti-topoisomerase (anti-Scl-70), which have been associated with increased cancer risk in these patients [9,10]. The temporal clustering and SSc autoantibodies linked to cancer indicate that there are shared and diverse molecular mechanisms involved in SSc-related cancer. PLOS One | https://doi.org/10.1371/journal.pone.0350006 May 27, 2026 2 / 18 However, our understanding of the molecular mechanisms underlying the pathological link is limited. The few Mendelian Randomization (MR) studies systematically examining the genetic overlap between SSc a (...truncated)