Frequent genetic alterations in myositis autoantigen genes in cancer-associated dermatomyositis

One-third of patients diagnosed with dermatomyositis harbour an occult cancer, a rare condition named cancer-associated dermatomyositis (CAD). Emerging evidence suggests that genetic alterations in autoantibody-related genes give rise to neoantigens and specific autoantibodies that initiate an autoimmune response characteristic of CAD. This study evaluated the prevalence of such genetic alterations and elucidated molecular mechanisms that may underlie their role in triggering autoimmunity.

Fifteen patients with CAD were included in the study. We conducted genomic and transcriptomic analyses of available leukocyte (germline), muscle, skin, and tumour samples. T-cell receptor (TCR) repertoire profiling and multiplex immunophenotyping were performed to characterise immune responses in tumoural and nontumoural tissues.

Somatic mutations and loss of heterozygosity (LOH) in autoantibody-related genes as tripartite motif containing 33, tripartite motif containing 66, MORC family CW-type zinc finger 3 (MORC3), Chromodomain Helicase DNA Binding Protein 4, and IFIH1, interferon-induced helicase C domain-containing protein 1-corresponding to known myositis-specific autoantibodies Anti-transcriptional intermediary factor 1 gamma, anti-nuclear matrix protein 2, (anti-transcriptional intermediary factor 1 gamma (anti-TIF1γ), anti-nuclear matrix protein 2 (anti-NXP2), anti-Mi2, antimelanoma differentiation-associated gene 5 protein), were detected in the majority of tumours from patients with CAD (75%). Tumour-specific missense mutations gave rise to highly immunogenic neoantigens, while LOH resulted in enriched allelic expression not observed in nontumoural lesions (skin and muscle). Immunophenotyping revealed a clonally expanded lymphocyte population within tumours, but not in nontumoural lesions, suggesting a distinct cellular immune response.

We detected highly frequent genetic alterations in autoantibody-related genes, supporting their role in the CAD pathogenic mechanisms. Moreover, our findings suggest that distinct TCR repertoire and immune signatures between tumoural and nontumoural tissues may underlie divergent cancer and dermatomyositis outcomes.