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Updated: Apr 14, 2026
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Oncogenic HER2 fusions in gastric cancer
De-Hua Yu1, Lili Tang2, Hua Dong3
1Innovation Center China, Asia & Emerging Market iMed, AstraZeneca Innovation Medicines and Early Development, 199 Liangjing Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China. yudehua@yahoo.com.
Background:
Genetic amplification of HER2 drives tumorigenesis and cancer progression in a subset of patients with gastric cancer (GC), and treatment with trastuzumab, a humanized HER2-neutralizing antibody, improves the overall survival rate of HER2-positive patients. However, a considerable portion of the patients does not respond to trastuzumab and the molecular mechanisms underlying the intrinsic resistance to anti-HER2 therapy in GC is not fully understood.
Methods:
We performed whole-transcriptome sequencing on 21 HER2-positive tumor specimens from Chinese GC patients. Whole genome sequencing was performed on the three samples with HER2 fusion to discover the DNA integration structure. A multicolor FISH assay for HER2 split screening was conducted to confirm HER2 fusion and IHC (HercepTest™) was used to detect the membranous expression of HER2. Fusion cDNA were transfected into NIH/3T3 cells and generate stable cell line by lentivirus. The expression of exogenous HER2 fusion proteins and pHER2 were examined by western blot analysis. In vitro efficacy studies were also conducted by PD assay and softagar assay in cell line expression wild type and fusion HER2. T-DM1 was used to assess its binding to NIH/3T3 cells ectopically expressing wild-type and fusion HER2. Finally, the anti-tumor efficacy of trastuzumab was tested in NIH/3 T3 xenografts expressing the HER2 fusion variants.
Results:
We identified three new HER2 fusions with ZNF207, MDK, or NOS2 in 21 HER2-amplified GC samples (14%; 3/21). Two of the fusions, ZNF207-HER2, and MDK-HER2, which are oncogenic, lead to aberrant activation of HER2 kinase. Treatment with trastuzumab inhibited tumor growth significantly in xenografts expressing MDK-HER2 fusion. In contrast, trastuzumab had no effect on the growth of xenografts expressing ZNF207-HER2 fusion, due to its inability to bind to trastuzumab.
Conclusions:
Our results provide the molecular basis of a novel resistance mechanism to trastuzumab-based anti-HER2 therapy, supporting additional molecule stratification within HER2-positive GC patients for more effective therapy options.
Insights
New HER2 fusions in gastric cancer (GC) can cause resistance to trastuzumab therapy. Identifying these fusions, like ZNF207-HER2, is key for developing more effective anti-HER2 treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genetic amplification of HER2 is a driver in a subset of gastric cancers (GC).
- Trastuzumab improves survival in HER2-positive GC, but intrinsic resistance limits its efficacy.
- Molecular mechanisms of trastuzumab resistance in GC are not fully understood.
Purpose of the Study:
- To investigate novel molecular mechanisms of resistance to anti-HER2 therapy in HER2-positive GC.
- To identify new HER2 fusions and characterize their oncogenic potential and response to trastuzumab.
Main Methods:
- Whole-transcriptome and whole-genome sequencing of HER2-positive GC tumor specimens.
- FISH assay to confirm HER2 fusions; IHC for HER2 expression.
- Functional studies in cell lines and xenografts to assess oncogenicity and drug response.
Main Results:
- Identified three novel HER2 fusions (ZNF207-HER2, MDK-HER2, NOS2-HER2) in 14% of HER2-amplified GC samples.
- ZNF207-HER2 and MDK-HER2 fusions were oncogenic, leading to aberrant HER2 kinase activation.
- Trastuzumab inhibited MDK-HER2 xenograft growth but not ZNF207-HER2 xenografts due to binding inability.
Conclusions:
- Discovered a novel resistance mechanism to trastuzumab involving specific HER2 fusions.
- Results support molecular stratification of HER2-positive GC patients for personalized therapy.
- Findings pave the way for more effective treatment strategies in refractory GC cases.
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