Internal Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain.
Medicine Department, Universitat Autónoma de Barcelona, Barcelona, Spain.
Rheumatology (Oxford). 2018 Feb 1;57(2):388-396. doi: 10.1093/rheumatology/kex413.
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).
Paired blood and tumour DNA samples from patients with anti-TIF1γ-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 TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score.
From seven patients with anti-TIF1γ-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 TIF1γ-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-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients.
Tumours from paraneoplastic anti-TIF1γ-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 TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.
分析基因改变和转录中介因子 1（TIF1）基因差异表达对癌症相关肌炎（CAM）病理生理学的影响。
对抗 TIF1γ 阳性 CAM 患者和对照组的配对血液和肿瘤 DNA 样本进行全外显子组测序，以分析其 TIF1 基因中是否存在体细胞突变和杂合性丢失（LOH）。根据免疫组织化学 H 评分，研究 TIF1γ 在 CAM 相关组织（皮肤、肌肉和肿瘤）中的表达，探讨自身免疫过程的发生和维持。
从 7 例抗 TIF1γ 阳性 CAM 患者中，我们在 4 个 TIF1 基因中的一个或多个基因中检测到 1 个体细胞突变和 5 例 LOH，而 TIF1γ 阴性肌炎患者的肿瘤中仅检测到 1 例 LOH（86%比 17%；P = 0.03）。与非肌炎患者的匹配对照肿瘤相比，抗 TIF1γ 阳性患者的 TIF1γ 染色更强烈（H 评分 255 比 196；P = 0.01）。此外，抗 TIF1γ 阳性肌炎患者的肌肉中 TIF1γ 染色略强于抗 TIF1γ 阴性肌炎（H 评分 22 比 5；P = 0.03）。相比之下，皮肤炎和对照患者的皮肤中都检测到强烈的 TIF1γ 染色。
在副肿瘤性抗 TIF1γ 阳性患者中，TIF1 基因的遗传改变（如突变和 LOH）数量增加。这些遗传改变，以及这些患者肿瘤、肌肉和皮肤中 TIF1γ 的高表达，可能是理解副肿瘤性肌炎发生的关键。
