Department of Dermatology, University Hospital Carl Gustav Carus at Technische Universität (TU) Dresden, Dresden, Germany.
National Center for Tumor Diseases (NCT), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
Br J Dermatol. 2021 Dec;185(6):1186-1199. doi: 10.1111/bjd.20604. Epub 2021 Aug 18.
Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate.
To investigate the drivers of EPC progression.
We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens.
mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years.
Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.
汗管癌（EPC）是一种罕见的皮肤癌，起源于外分泌汗腺。由于缺乏有效的治疗方法，转移与高死亡率相关。
研究 EPC 进展的驱动因素。
我们对转移性 EPC（mEPC）进行了基因组和转录组分析，在一个 EPC 患者来源的细胞系中验证了观察到的改变，在一个包含 30 个肿瘤组织的大型患者队列中确认了相关观察结果，并根据确定的治疗方案成功治疗了一名 mEPC 患者。
mEPC 的特点是高肿瘤突变负担（TMB），具有紫外线特征，广泛的拷贝数改变和基因表达变化，影响癌症相关的细胞过程，如细胞周期调节和增殖，包括致病性 TP53（肿瘤蛋白 53）突变、CDKN2A（细胞周期蛋白依赖性激酶抑制剂 2A）区域的拷贝数缺失和 CTNND1/PAK1 [连接蛋白 delta 1/p21（RAC1）激活激酶 1]基因融合。EGFR（表皮生长因子受体）、PAK1 和 MAP2K1（丝裂原活化蛋白激酶激酶 1；也称为 MEK1）基因的过表达转化为肿瘤组织中强烈的蛋白表达和各自的途径激活。此外，患者来源的细胞系对 EGFR 和 MEK 抑制敏感，证实了途径激活的功能相关性。在一个大型患者队列中的免疫组织化学分析表明，观察到的变化与 EPC 的发病机制相关。我们的结果表明，mEPC 应该对免疫或激酶抑制剂治疗有反应。事实上，我们的指数患者的晚期疾病通过 EGFR 靶向治疗和免疫检查点抑制控制了超过 2 年。
分子谱分析表明，高 TMB 和 EGFR/MAPK 途径激活是 mEPC 的新治疗靶点。
