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

Int J Cancer. 2016 Jan 1;138(1):195-205. doi: 10.1002/ijc.29676. Epub 2015 Jul 22.


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.

Keywords: Notch1; biomarker; colorectal cancer.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Biomarkers, Tumor
  • Calcium-Binding Proteins / metabolism
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality*
  • Colorectal Neoplasms / pathology
  • DNA Copy Number Variations*
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Dosage*
  • Gene Duplication
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Metastasis
  • Prognosis
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Biomarkers, Tumor
  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • Receptor, Notch1
  • Serrate-Jagged Proteins