Genetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: Its association with clinicopathologic features
Genetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: Its association with clinicopathologic features
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DOI：
10.1158/1078-0432.ccr-05-0293
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发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Shibata, T;Uryu, S;Hirohashi, S
使用微阵列细菌人工染色体克隆的基于阵列的比较基因组杂交可以高分辨率地分析肿瘤全基因组拷贝数的变化。为了高通量地分析原发性肺腺癌的遗传变化，我们采用了激光捕获癌细胞显微切割和阵列比较基因组杂交的方法，重点研究了800个包含癌症相关基因的染色体基因座。我们发现了大量的染色体数目改变，包括7p12、11q13、12q14-15和17q21的频繁扩增，以及9p21上的两个纯合子缺失和8p23上的一个纯合缺失。对多重改变的非监督等级聚类分析显示，肺腺癌有三个亚型，其特征是累积了明显的基因改变，并与吸烟史和性别有关。表皮生长因子受体(EGFR)基因的突变状态与特定的基因改变显著相关，基于EGFR基因突变的监督聚类分析揭示了包括所有EGFR基因突变的肿瘤的亚组，这表明无病生存时间显著缩短。我们的结果提示，肺腺癌存在多种分子致癌途径，可能与吸烟习惯和性别有关，基因癌变图谱将揭示癌症以前未知的遗传异质性，有助于估计患者预后和发现新的癌症相关基因，包括治疗靶点。
The array-based comparative genomic hybridization using microarrayed bacterial artificial chromosome clones allows high-resolution analysis of genome-wide copy number changes in tumors. To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, we used laser-capture microdissection of cancer cells and array comparative genomic hybridization focusing on 800 chromosomal loci containing cancer-related genes. We identified a large number of chromosomal numerical alterations, including frequent amplifications on 7p12, 11q13,12q14-15, and 17q21, and two homozygous deletions on 9p21 and one on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed three subgroups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history and gender. The mutation status of the epidermal growth factor receptor (EGFR) gene was significantly associated with specific genetic alterations and supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival. Our results suggest that there exist multiple molecular carcinogenesis pathways in lung adenocarcinoma that may associate with smoking habits and gender, and that genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patient prognosis and discovering novel cancer-related genes including therapeutic targets.