ANOTCH1gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer

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.

MicroRNA‐30a as a prognostic factor in urothelial carcinoma of bladder inhibits cellular malignancy by antagonising Notch1

“…One previous study from our laboratories on the Notch signalling pathway, preliminarily found that Notch1 acts as an oncogene in UCB . In various studies concerning other types of tumours, Notch signalling also shows oncogenic function . It has been widely acknowledged that Notch mediators include the Hes family, Hey family, nuclear factor‐κB, vascular growth factor receptor , and there are other Notch mediators yet to be discovered.…”

High expression of the Notch ligand Jagged‐1 is associated with poor prognosis after surgery for colorectal cancer

“…(3)(4)(5)(6)(7)(8) Additionally, it has been shown that Notch signaling is strongly activated in primary human colorectal cancer (CRC) and has an important role in the initiation and progression of CRC through the regulation of apoptosis, proliferation, angiogenesis and cell migration. (9)(10)(11)(12)(13)(14) Recent reports have also indicated that JAG1 mediates the activation of Notch signaling in CRC and induces CRC progression. (15)(16)(17)(18)(19) Thus, the JAG1-Notch pathway has been regarded an attractive target for CRC therapy.Although high expression of JAG1 and the prognostic implications of Notch receptors in cancer cells have been described, (11)(12)(13)(14)(16)(17)(18)(19)(20) the prognostic significance of high JAG1 expression in CRC has not been determined.…”

“…(9)(10)(11)(12)(13)(14) Recent reports have also indicated that JAG1 mediates the activation of Notch signaling in CRC and induces CRC progression. (15)(16)(17)(18)(19) Thus, the JAG1-Notch pathway has been regarded an attractive target for CRC therapy.Although high expression of JAG1 and the prognostic implications of Notch receptors in cancer cells have been described, (11)(12)(13)(14)(16)(17)(18)(19)(20) the prognostic significance of high JAG1 expression in CRC has not been determined. Therefore, we investigated the association of JAG1 protein expression with survival and recurrence in CRC by immunohistochemistry (IHC) using postoperative specimens and survey information on CRC prognosis collected in our research institute.…”

“…Although high expression of JAG1 and the prognostic implications of Notch receptors in cancer cells have been described, (11)(12)(13)(14)(16)(17)(18)(19)(20) the prognostic significance of high JAG1 expression in CRC has not been determined. Therefore, we investigated the association of JAG1 protein expression with survival and recurrence in CRC by immunohistochemistry (IHC) using postoperative specimens and survey information on CRC prognosis collected in our research institute.…”

NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors?

“…It also positively regulated the proliferation, colony formation, cell cycling, and tumorsphere formation of human colon cancers [106]. The elevated copy number gain of NOTCH1 together with its mRNA overexpression made it an independent predictor of prognosis in CRC [107, 108]. In colorectal carcinoma cells, NOTCH1-deppendent activation of cell cycle and proliferation were mediated by repression of cyclin-dependent kinase inhibitor p27.…”