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

Abstract

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.

• Authors: Ziliang Qian, Guanshan Zhu, Lili Tang, Mei Wang, Lianhai Zhang, Jiangang Fu, Chunlei Huang, Shuqiong Fan, Yun Sun, Jing Lv, Hua Dong, Beirong Gao, Xinying Su, Dehua Yu, Jie Zang, Xiaolin Zhang, Jiafu Ji, Qunsheng Ji
• Journal: Genes, chromosomes & cancer (Genes Chromosomes Cancer) Vol. 53 Issue 11 Pg. 883-94 (Nov 2014) ISSN: 1098-2264 [Electronic] United States
• PMID: 24935174 (Publication Type: Journal Article)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• AZD 6244
• Benzimidazoles
• KRAS protein, human
• Proto-Oncogene Proteins
• RNA, Messenger
• MAP2K2 protein, human
• PAK1 protein, human
• p21-Activated Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Benzimidazoles (pharmacology)
• Chromosomal Instability
• Cohort Studies
• Female
• Gene Amplification
• Gene Dosage
• Gene Expression Profiling
• Genome, Human
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Male
• Middle Aged
• Mutation
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras)
• RNA, Messenger (metabolism)
• Stomach Neoplasms (genetics, metabolism, mortality)
• Survival Rate
• p21-Activated Kinases (genetics, metabolism)
• ras Proteins (genetics, metabolism)