Genomic predictors of interindividual differences in response to DNA damaging agents

  1. Rebecca C. Fry1,2,3,4,6,
  2. J. Peter Svensson1,2,6,
  3. Chandni Valiathan1,2,3,6,
  4. Emma Wang1,2,
  5. Brad J. Hogan1,2,
  6. Sanchita Bhattacharya2,7,
  7. James M. Bugni1,2,
  8. Charles A. Whittaker2,3, and
  9. Leona D. Samson1,2,3,4,5,8
  1. 1 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  2. 2 Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  3. 3 Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  4. 4 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  5. 5 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  1. 6

    6 These authors contributed equally to this work.

Abstract

Human lymphoblastoid cells derived from different healthy individuals display considerable variation in their transcription profiles. Here we show that such variation in gene expression underlies interindividual susceptibility to DNA damaging agents. The results demonstrate the massive differences in sensitivity across a diverse cell line panel exposed to an alkylating agent. Computational models identified 48 genes with basal expression that predicts susceptibility with 94% accuracy. Modulating transcript levels for two member genes, MYH and C21ORF56, confirmed that their expression does indeed influence alkylation sensitivity. Many proteins encoded by these genes are interconnected in cellular networks related to human cancer and tumorigenesis.

Keywords

Footnotes

  • 7

    7 Present address: Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

  • 8

    8 Corresponding author.

    8 E-MAIL lsamson{at}mit.edu; FAX (617) 253-8099.

  • Supplemental material is available at http://www.genesdev.org.

  • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1688508.

    • Received April 24, 2008.
    • Accepted August 7, 2008.
  • Freely available online through the Genes & Development Open Access option.

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