Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets

• Published in: Genes chromosomes & cancer Vol. 53; no. 11; pp. 883 - 894
• Main Authors: Qian, Ziliang, Zhu, Guanshan, Tang, Lili, Wang, Mei, Zhang, Lianhai, Fu, Jiangang, Huang, Chunlei, Fan, Shuqiong, Sun, Yun, Lv, Jing, Dong, Hua, Gao, Beirong, Su, Xinying, Yu, Dehua, Zang, Jie, Zhang, Xiaolin, Ji, Jiafu, Ji, Qunsheng
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-11-2014; Wiley Subscription Services, Inc
• Subjects: Benzimidazoles - pharmacology; Chromosomal Instability; Cohort Studies; Female; Gene Amplification; Gene Dosage; Gene Expression Profiling; Genome, Human; Humans; Male; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 2 - antagonists & inhibitors; Middle Aged; Mutation; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; ras Proteins - metabolism; RNA, Messenger - metabolism; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - mortality; Survival Rate
• ISSN: 1045-2257; 1098-2264
• DOI: 10.1002/gcc.22196

Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5‐year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole‐genome analysis of 131 Chinese gastric cancer tissue specimens using whole‐genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, PAK1, STARD13, KRAS, and ABCC4, in addition to ERBB2, FGFR2, and MET. The growth of PAK1‐amplified gastric cancer cells in vitro and in vivo was inhibited when the corresponding mRNA was knocked down. Furthermore, both KRAS amplification and KRAS mutation were identified in the gastric cancer specimens. KRAS amplification was associated with worse clinical outcomes, and the KRAS gene mutation predicted sensitivity to the MEK1/2 inhibitor AZD6244 in gastric cancer cell lines. In summary, amplified PAK1, as well as KRAS amplification/mutation, may represent unique opportunities for developing targeted therapeutics for the treatment of gastric cancer. © 2014 Wiley Periodicals, Inc.