A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer

John J. Arcaroli, W. M. Tai, Ryan Mcwilliams, Stacey Bagby, Patrick J. Blatchford, Marileila Varella-Garcia, Alicia Purkey, Kevin S. Quackenbush, Eun Kee Song, Todd M. Pitts, Dexiang Gao, Chris Lieu, Martine Mcmanus, Aik-Choon Tan, Xianxian Zheng, Qin Zhang, Mark Ozeck, Peter Olson, Zhi Qin Jiang, Scott KopetzAntonio Jimeno, Stephen Keysar, Gail Eckhardt, Wells A. Messersmith

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes. What's new? There is mounting evidence that the Notch1 receptor is important in modulating tumor growth and an independent predictor of survival in colorectal cancer (CRC). While mutations in the NOTCH1 receptor have not yet been described in CRC, this study shows that a gain in NOTCH1 gene copy number is associated with worse survival. Targeting cells with a specific Notch1 antibody resulted in potent antitumor growth in a CRC patient-derived tumor xenograft model. A NOTCH1 gene copy number gain may thus be a prognostic marker for disease recurrence as well as a predictive biomarker of sensitivity to a Notch1 targeted therapy.

Original languageEnglish
Pages (from-to)195-205
Number of pages11
JournalInternational Journal of Cancer
Volume138
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1
Externally publishedYes

Keywords

  • biomarker
  • colorectal cancer
  • Notch1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Arcaroli, J. J., Tai, W. M., Mcwilliams, R., Bagby, S., Blatchford, P. J., Varella-Garcia, M., Purkey, A., Quackenbush, K. S., Song, E. K., Pitts, T. M., Gao, D., Lieu, C., Mcmanus, M., Tan, A-C., Zheng, X., Zhang, Q., Ozeck, M., Olson, P., Jiang, Z. Q., ... Messersmith, W. A. (2016). A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer. International Journal of Cancer, 138(1), 195-205. https://doi.org/10.1002/ijc.29676