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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(s) -
Arcaroli John J.,
Tai W.M.,
McWilliams Ryan,
Bagby Stacey,
Blatchford Patrick J.,
VarellaGarcia Marileila,
Purkey Alicia,
Quackenbush Kevin S.,
Song EunKee,
Pitts Todd M.,
Gao Dexiang,
Lieu Chris,
McManus Martine,
Tan Aik Choon,
Zheng Xianxian,
Zhang Qin,
Ozeck Mark,
Olson Peter,
Jiang ZhiQin,
Kopetz Scott,
Jimeno Antonio,
Keysar Stephen,
Eckhardt Gail,
Messersmith Wells A.
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29676
Subject(s) - colorectal cancer , copy number variation , gene duplication , biomarker , gene dosage , medicine , oncology , cancer research , cancer , gene , biology , gene expression , genetics , genome
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.