Abstract

Alterations in EGFR, PDGF, INK4a, p53 and/or PTEN are among the most common lesions encountered in malignant gliomas. Notably, a significant proportion of malignant gliomas do not harbor these signature genetic lesions, implying that many other glioma relevant mutations remain unidentified. Recent advances in functional genomics have provided new capabilities for the rapid identification and characterization of candidate glioma-relevant genes and their pathways. Taking advantage of the presence of recurrent chromosomal alterations associated with amplification or deletion of specific genes in malignant gliomas, array-based CGH technique has identified five high-frequency regions of gains. Employing the newly optimized array-based CGH on cDNA microarray platform, we will finely map and characterize these five loci of chromosomal aberrations to identify all candidate genes within the minimal regions of involvement. Complemented with various expression - based analyses, we will identify the most likely targets of CNAs for in vitro and in vivo functional validation. The highest potential candidate glioma oncogene will be further validated by rigorous in vivo transgenesis study.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA099041-01A1
Application #
6688068
Study Section
Special Emphasis Panel (ZRG1-CPA (02))
Program Officer
Okano, Paul
Project Start
2003-09-24
Project End
2008-07-31
Budget Start
2003-09-24
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$304,380
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Chen, An-Jou; Paik, Ji-Hye; Zhang, Hailei et al. (2012) STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA. Genes Dev 26:1459-72
Ying, Haoqiang; Zheng, Hongwu; Scott, Kenneth et al. (2010) Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc Natl Acad Sci U S A 107:6912-7
Zheng, Hongwu; Ying, Haoqiang; Wiedemeyer, Ruprecht et al. (2010) PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 17:497-509
Stegh, Alexander H; Brennan, Cameron; Mahoney, John A et al. (2010) Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor. Genes Dev 24:2194-204
Paulson, Kelly G; Lemos, Bianca D; Feng, Bin et al. (2009) Array-CGH reveals recurrent genomic changes in Merkel cell carcinoma including amplification of L-Myc. J Invest Dermatol 129:1547-55
Stegh, Alexander H; Chin, Lynda; Louis, David N et al. (2008) What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator. Cell Cycle 7:2833-9
Jeon, Hye-Min; Jin, Xun; Lee, Joong-Seob et al. (2008) Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling. Genes Dev 22:2028-33
Stegh, Alexander H; Kesari, Santosh; Mahoney, John E et al. (2008) Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. Proc Natl Acad Sci U S A 105:10703-8
Protopopov, Alexei; Feng, Bin; Chin, Lynda (2008) Full complexity genomic hybridization on 60-mer oligonucleotide microarrays for array comparative genomic hybridization (aCGH). Methods Mol Biol 439:87-100
Kimmelman, Alec C; Hezel, Aram F; Aguirre, Andrew J et al. (2008) Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci U S A 105:19372-7

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