Tumour TIF1 mutations and loss of heterozygosity related to cancer-associated myositis

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Objectives. To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM). Methods. Paired blood and tumour DNA samples from patients with anti-TIFγ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIFγ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score. Results. From seven patients with anti-TIFγ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIFγ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIFγ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIFγ staining in muscle was slightly more intense in anti-TIFγpositive than in anti-TIFγ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIFγ staining was detected in the skin of both myositis and control patients. Conclusion. Tumours from paraneoplastic anti-TIFγ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIFγ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.