Clustered genomic alterations in chromosome 7p dictate outcomes and targeted treatment responses of lung adenocarcinoma with EGFR-activating mutations

Shinsheng Yuan, Sung Liang Yu, Hsuan Yu Chen, Yi Chiung Hsu, Kang Yi Su, Huei Wen Chen, Chih Yi Chen, Chong Jen Yu, Jin Yuan Shih, Yih Leong Chang, Chiou Ling Cheng, Chung Ping Hsu, Jiun Yi Hsia, Chien Yu Lin, Guani Wu, Chia Hsin Liu, Chin Di Wang, Kang Chung Yang, Yi Wei Chen, Yi Ling LaiChu Chun Hsu, Tai Ching Lin, Tsung Ying Yang, Kun Cheieh Chen, Kuo Hsuan Hsu, Jeremy J.W. Chen, Gee Chen Chang, Ker Chau Li, Pan Chyr Yang

研究成果: 雜誌貢獻期刊論文同行評審

26 引文 斯高帕斯(Scopus)

摘要

Purpose: Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. Patients and Methods: We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. Results: We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. Conclusion: Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.

原文???core.languages.en_GB???
頁(從 - 到)3435-3442
頁數8
期刊Journal of Clinical Oncology
29
發行號25
DOIs
出版狀態已出版 - 1 9月 2011

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