Genetic and epigenetic analysis of erbB signaling pathway genes in lung cancer.
Genetic and epigenetic analysis of erbB signaling pathway genes in lung cancer.
复制标题
DOI：
10.1097/jto.0b013e3181f77a53
复制
发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Sidransky D
中科院分区：
文献类型：
--
作者：
Hoque MO;Brait M;Rosenbaum E;Poeta ML;Pal P;Begum S;Dasgupta S;Carvalho AL;Ahrendt SA;Westra WH;Sidransky D
非小细胞肺癌（NSCLC）患者的预后很差。最近批准的抑制其活性的特定药物反映了调节EGFR用于治疗的潜在价值。在肺癌中报告了EGFR突变，并且一旦它们能够识别可能对各种靶向小分子有反应的肺癌，就引起了人们的兴趣。我们在一系列原发性NSCLC [共111例;腺癌49例，鳞状细胞癌（SCC）48例和其他14例]中检测了该通路的3种关键遗传和表观遗传学改变（EGFR、RASSF 1A和BRAF）。已知这些样本的KRAS（和p53）突变状态。本研究的目的是确定非小细胞肺癌中erbB通路改变的模式，并检测其与临床参数的相关性。确定了5种EGFR突变：腺癌3种（6%），SCC 1种（2%），腺癌伴支气管肺泡成分肿瘤1种（7%）。EGFR突变包括外显子19的3个框内缺失和外显子21的2个点突变。RASSF 1A基因启动子甲基化在45例腺癌中有25例，在46例SCC中有18例。腺癌中EGFR、BRAF和KRAS突变相互排斥，与RASSF 1A甲基化呈负相关（p =-0.394; p=0.007）。总体而言，在80%（39/49）的腺癌中检测到erbB通路基因的遗传和/或表观遗传学改变。近一半的原发性腺癌具有erbB通路的分子改变。需要仔细描述这些改变和抗EGFR治疗的反应，以确定更好和准确的临床反应决定因素。
Prognosis for patients with non-small cell lung cancer (NSCLC) is poor. The potential value of modulating EGFR for treatment is reflected by the recent approval of specific drugs that inhibit its activity. Mutations in EGFR were reported in lung cancer and generated interest, once they enable the identification of lung cancers likely to respond to various targeted small molecules. We tested 3 key genetic and epigenetic alterations (EGFR, RASSF1A, and BRAF) of this pathway on a series of primary NSCLC [Total 111; adenocarcinoma 49, squamous cell carcinoma (SCC) 48 and others 14]. The mutational status of KRAS (and p53) was known for these samples. The purpose of this study was to define the pattern of erbB pathway alterations in NSCLC and to test for associations with clinical parameters. Five EGFR mutations were identified: 3 in adenocarcinoma (6 %), 1 in SCC (2%) and 1 in adenocarcinoma with bronchoalveolar component tumor (7%). EGFR mutations included 3 in-frame deletions in exon 19 and 2 point mutations in exon 21. Promoter methylation of RASSF1A was detected in 25 of 45 adenocarcinomas and 18 of 46 SCC. Mutations of EGFR, BRAF and KRAS in adenocarcinoma were mutually exclusive and inversely correlated with RASSF1A methylation (p = −0.394; p=0.007). Overall, genetic and/or epigenetic alterations of erbB pathway genes were detected in 80% (39/49) of adenocarcinomas. Nearly half of primary adenocarcinoma harbor molecular alterations of the erbB pathway. Careful characterization of these alterations and response to anti-EGFR therapies is warranted to determine better and accurate determinants of clinical response.