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

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.

Author information

1
Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
2
Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
3
Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA.
4
MD Anderson Cancer Center, Texas Medical Center, Houston, TX.

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.

KEYWORDS:

Notch1; biomarker; colorectal cancer

PMID:
26152787
PMCID:
PMC4618491
DOI:
10.1002/ijc.29676
[Indexed for MEDLINE]
Free PMC Article

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