Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification

Shuaili Chen, Theresa Auletta, Ostap Dovirak, Christina Hutter, Karen Kuntz, Samira El-ftesi, Jude Kendall, Haiyong Han, Daniel D. Von Hoff, Raheela Ashfaq, Anirban Maitra, Christine A. Iacobuzio-Donahue, Ralph H. Hruban, Robert Lucito

Research output: Contribution to journalArticle

Abstract

Pancreatic cancer is one of the most lethal of all cancers. The median survival is 6 months, and less than 5% of those diagnosed survive 5-years. Recurrent genetic deletions and amplifications in 72 pancreatic adenocarcinomas, the largest sample set analyzed to date for pancreatic cancer, were defined using comparative genomic hybridization The recurrent genetic alterations identified target a number of previously well-characterized genes, as well as regions that contain possible new oncogenes and tumor suppressor genes. We have focused on chromosome 19q13, a region frequently found amplified in pancreatic cancer, and demonstrate how boundaries of common regions of mutation can be mapped, and how a gene, in this case PAK4 amplified on chromosome 19q13, can be functionally validated. We show that although the PAK4 gene is not activated by mutation in cell lines with gene amplification, an oncogenic form of the KRAS2 gene is present in these cells, and oncogenic KRAS2 can activate PAK4. In fact in the three samples we identified with PAK4 gene amplification, the KRAS2 gene was activated and genomically amplified. The kinase activity of the PAK4 protein is significantly higher in cells with genomic amplification as compared to cells without amplification. Our study demonstrates the utility of analyzing copy number data in a large set of neoplasms to identify genes involved in cancer. We have generated a useful dataset which will be particularly useful for the pancreatic cancer community as efforts are undertaken to sequence the pancreatic cancer genome.

Original languageEnglish (US)
Pages (from-to)1793-1802
Number of pages10
JournalCancer Biology and Therapy
Volume7
Issue number11
DOIs
StatePublished - Nov 2008

Keywords

  • Amplification
  • CGH
  • Cancer
  • Deletion
  • Genomics
  • Pak4
  • Pancreactic

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint Dive into the research topics of 'Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification'. Together they form a unique fingerprint.

  • Cite this

    Chen, S., Auletta, T., Dovirak, O., Hutter, C., Kuntz, K., El-ftesi, S., Kendall, J., Han, H., Von Hoff, D. D., Ashfaq, R., Maitra, A., Iacobuzio-Donahue, C. A., Hruban, R. H., & Lucito, R. (2008). Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biology and Therapy, 7(11), 1793-1802. https://doi.org/10.4161/cbt.7.11.6840