Background/Purpose: To analyze the influence of genetic alterations and differential expression of the TIF1 genes in the pathophysiology of cancer-associated myositis (CAM).

Methods: Whole exome sequencing of paired blood and tumor DNA samples from anti-TIF1g positive CAM patients and controls were analyzed for the presence of somatic mutations and copy number changes in the TIF1 genes. To better understand the genesis and maintenance of the autoimmune process we also studied the expression of TIF1g in the different tissues involved in CAM (skin, muscle, and tumor) calculating the immunohistochemical H-score.

Results: Six out of 7 tumors from anti-TIF1g positive patients showed somatic mutations or loss of heterozygosity in one or more of the 4 TIF1 genes compared with just one myositis control tumor (86% vs. 17%, p=0.03). Compared with control tumors from non-myositis patients, tumors from both anti-TIF1g positive (H-score 255 vs. 196, p=0.01) and anti-TIF1g negative CAM patients (H-score 251 vs. 152, p=0.03) showed more intense TIF1g staining, without significant differences between anti-TIF1g positive and negative patients. Compared with anti-TIF1g negative patients, TIF1g muscle staining was more intense in anti-TIF1g positive patients (H-score 22 vs. 5, p=0.03), while the skin of both myositis and control patients showed intense TIF1g staining.

Conclusion: Mutations of TIF1 genes in tumors with high expression of TIFg may trigger myositis. We hypothesize that an intense antineoplastic immune response may cause a rapid depletion of tumor neo-antigen shifting the target of immune cells experiencing affinity maturation towards the wild-type form of the antigen, abundantly expressed in the skin and muscle of these patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tumor-tif1-mutations-and-loss-of-heterozygosity-related-to-cancer-associated-myositis/