CD74-NRG1 Fusions in Lung Adenocarcinoma
CD74-NRG1 Fusions in Lung Adenocarcinoma
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DOI：
10.1158/2159-8290.cd-13-0633
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发表时间：
2014-04-01
期刊：
影响因子：
28.2
通讯作者：
Thomas, Roman K.
中科院分区：
文献类型：
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作者：
Fernandez-Cuesta, Lynnette;Plenker, Dennis;Thomas, Roman K.
我们通过对25例从不吸烟的肺腺癌进行转录组测序，发现了一种新的体细胞基因融合体CD 74-NRG 1。通过筛选102例已知致癌改变阴性的肺腺癌，我们发现了另外4例融合阳性肿瘤，均为浸润性粘液亚型。在机制上，CD 74-NRG 1导致NRG 1 III-β 3的EGF样结构域的细胞外表达，从而为ERBB 2-ERBB 3受体复合物提供配体。因此，ERBB 2和ERBB 3在指示病例中表达较高，并且磷酸化ERBB 3的表达在具有融合的肿瘤中特异性地发现（P < 0.0001）。在表达ERBB 2和ERBB 3的肺癌细胞系中，CD 74-NRG 1的异位表达激活了ERBB 3和PI 3 K-AKT通路，并导致软琼脂中集落形成增加。因此，CD 74-NRG 1基因融合激活浸润性粘液腺癌的基因组改变，并可能为肺肿瘤亚型提供治疗机会，到目前为止，没有有效的treatment.Significance：CD 74-NRG 1融合可能代表一个治疗机会，浸润性粘液肺腺癌，肿瘤没有有效的治疗，经常提出与多灶性不可切除的疾病。Cancer Discov; 4（4）; 415- 22. (c)2014年AACR。
We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III- ss 3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion ( P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.SIGNIFICANCE: CD74-NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415- 22. (c) 2014 AACR.