文章：

全外显子组测序显示有希望的治疗策略

Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies 

原文发布日期：2021-05-27 

英文摘要：

Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. Recurrent driving somatic alterations were detected in the EP candidate drivers TP53, FAT2, CACNA1S, and KMT2D. The analyses also identified copy number alterations and recurrent gains and losses in several chromosomal regions including that containing BRCA2, as well as deleterious alterations in multiple HRR components. In accordance with this reduced or even a complete loss of BRCA2 protein expression was detected in 50% of the investigated EP tumours. Our results implicate crucial oncogenic driver pathways and suggest that defective homologous double-strand break repair and the p53 pathway are involved in EP aetiology. Targeting of the p53 axis and PARP inhibition, and/or immunotherapy may represent promising treatment strategies. 

摘要翻译： 

恶性汗腺肿瘤较为罕见，其中最常见的是小汗腺孔癌（EP）。为探究EP的突变谱，我们对14例福尔马林固定石蜡包埋的匹配原发性EP样本及周围健康组织进行了全外显子组测序（WES）。突变分析显示总体中位突变率较高，这与紫外线（UV）暴露、APOBEC酶功能失调以及同源双链断裂修复缺陷相关的突变过程特征有关——这些过程均会导致基因组不稳定性并参与致癌机制。研究在EP候选驱动基因TP53、FAT2、CACNA1S和KMT2D中检测到反复出现的驱动性体细胞突变，同时发现多个染色体区域（含BRCA2基因区域）存在拷贝数变异及反复增减现象，并观察到同源重组修复（HRR）多个组分的有害突变。与此一致的是，在50%的研究EP肿瘤中检测到BRCA2蛋白表达降低甚至完全缺失。我们的研究结果揭示了关键致癌驱动通路，表明同源双链断裂修复缺陷和p53通路参与EP的发病机制。针对p53轴的通路调控、PARP抑制剂和/或免疫治疗可能成为具有潜力的治疗策略。

原文链接：

Whole-exome sequencing in eccrine porocarcinoma indicates promising therapeutic strategies