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.

Autor: Arcaroli JJ; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Tai WM; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., McWilliams R; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Bagby S; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Blatchford PJ; Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Varella-Garcia M; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Purkey A; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Quackenbush KS; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Song EK; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Pitts TM; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Gao D; Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Lieu C; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., McManus M; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Tan AC; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Zheng X; Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA., Zhang Q; Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA., Ozeck M; Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA., Olson P; Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA., Jiang ZQ; MD Anderson Cancer Center, Texas Medical Center, Houston, TX., Kopetz S; MD Anderson Cancer Center, Texas Medical Center, Houston, TX., Jimeno A; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Keysar S; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Eckhardt G; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO., Messersmith WA; Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2016 Jan 01; Vol. 138 (1), pp. 195-205. Date of Electronic Publication: 2015 Jul 22.
DOI: 10.1002/ijc.29676
Abstrakt: 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.
(© 2015 UICC.)
Databáze: MEDLINE
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