KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung
KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung
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DOI：
10.1016/j.jtho.2016.01.010
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发表时间：
2016-04-01
影响因子：
20.4
通讯作者：
Dong, Fei
中科院分区：
文献类型：
--
作者：
Hwang, David H.;Sholl, Lynette M.;Dong, Fei
简介：在具有独特临床和病理特征的肺腺癌中观察到粘液分化，但对这些肿瘤的生物学知之甚少。方法：我们应用靶向的下一代测序来表征21种浸润性粘液腺癌、混合性粘液/非粘液腺癌、和肺粘液特征的腺癌，并验证了来自我们机构的954例额外肺腺癌和来自癌症基因组图谱的514例肺腺癌的关键发现。测序鉴定了致癌基因Kirsten大鼠肉瘤病毒致癌基因同源物（KRAS）、磷脂酰肌醇-4，5-二磷酸3-激酶催化亚基α（PIK 3CA）、erb-b2受体酪氨酸激酶2（ERBB 2）和间变性淋巴瘤受体酪氨酸激酶（ALK）中的致病性突变以及肿瘤蛋白p53（TP 53）中的复发性突变，丝氨酸/苏氨酸激酶11（STK 11）、NK 2同源框1（NKX 2 -1）和含SET结构域2（SETD 2）。在结合发现和验证队列中，我们确定了9种具有不同分子和病理特征的肿瘤。所有病例均为浸润性粘液腺癌或混合性粘液/非粘液腺癌，伴有KRAS突变和NKX 2 -1移码或无义突变。免疫组化分析表明，这些肿瘤与分化状态的改变，包括肺标志物甲状腺转录因子1（也称为NKX2.1）的表达和胃肠markets.Conclusions表达的损失：这些研究结果描述了复发NKX 2 -1突变浸润性粘液腺癌的肺和支持NKX 2 -1作为一个谱系特异性肿瘤抑制基因在肺癌发生。(C)2016年国际肺癌研究协会。由爱思唯尔公司出版All rights reserved.
Introduction: Mucinous differentiation is observed in a subset of lung adenocarcinomas with unique clinical and pathological features, but the biology of these neoplasms is poorly understood.Methods: We apply targeted next-generation sequencing to characterize the mutational profiles of 21 invasive mucinous adenocarcinomas, mixed mucinous/nonmucinous adenocarcinomas, and adenocarcinomas with mucinous features of the lung and validate key findings on 954 additional lung adenocarcinomas from our institution and 514 lung adenocarcinomas from The Cancer Genome Atlas.Results: Sequencing identifies pathogenic mutations in the oncogenes Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), erb-b2 receptor tyrosine kinase 2 (ERBB2), and anaplastic lymphoma receptor tyrosine kinase (ALK) and recurrent mutations in tumor protein p53 (TP53), serine/threonine kinase 11 (STK11), NK2 homeobox 1 (NKX2-1), and SET domain containing 2 (SETD2). In the combined discovery and validation cohorts, we identify nine neoplasms with distinct molecular and pathological features. All are invasive mucinous adenocarcinomas or mixed mucinous/nonmucinous adenocarcinomas with mutations of KRAS and frameshift or nonsense mutations of NKX2-1. Immunohistochemical analysis shows that these neoplasms are associated with altered differentiation states, including loss of expression of the pulmonary marker thyroid transcription factor 1 (also called Nkx2.1) and expression of gastrointestinal markers.Conclusions: These findings describe recurrent NKX2-1 mutations in invasive mucinous adenocarcinomas of the lung and support NKX2-1 as a lineage-specific tumor suppressor gene in lung carcinogenesis. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.