title: 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.affiliation: Innovation Centre China, Asia & Emerging Market iMed, AstraZeneca Innovation Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic Of China.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Qian
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.forename: Lili
authors.initials: L
authors.lastname: Tang
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Lianhai
authors.initials: L
authors.lastname: Zhang
authors.forename: Jiangang
authors.initials: J
authors.lastname: Fu
authors.forename: Chunlei
authors.initials: C
authors.lastname: Huang
authors.forename: Shuqiong
authors.initials: S
authors.lastname: Fan
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.forename: Jing
authors.initials: J
authors.lastname: Lv
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Beirong
authors.initials: B
authors.lastname: Gao
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.forename: Dehua
authors.initials: D
authors.lastname: Yu
authors.forename: Jie
authors.initials: J
authors.lastname: Zang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Jiafu
authors.initials: J
authors.lastname: Ji
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D043171:Chromosomal Instability; D015331:Cohort Studies; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C482128:MAP2K2 protein, human; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins