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Updated: Apr 18, 2026
Methyl-binding DNA capture Sequencing for Patient Tissues
Published on: October 31, 2016
Comprehensive DNA Methylation and Extensive Mutation Analyses of HER2-Positive Breast Cancer
Takeshi Yamaguchi1, Hirofumi Mukai, Satoshi Yamashita
1Department of Medical Oncology, Musashino Red Cross Hospital, Tokyo, Japan.
Objective:
Resistance to trastuzumab is a problem that remains to be solved in HER2-positive breast cancer. We aimed to characterize profiles of genetic and epigenetic alterations in cancer-related pathways in HER2-positive breast cancers, using biopsy tissue samples obtained from patients enrolled in a prospective neoadjuvant clinical trial.
Methods:
HER2-positive breast cancer tissue samples were collected and processed with the PAXgene Tissue System. A total of 24 breast cancers were analyzed. Genetic alterations of 409 cancer-related genes were analyzed by a bench-top next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes.
Results:
The WNT pathway was potentially activated by aberrant methylation of its negative regulators, such as DKK3 and SFRP1, in 9 breast cancers. The AKT/mTOR pathway was activated by mutations of PIK3CA in 5 breast cancers. The Notch pathway was potentially activated by mutations of NOTCH1 and NOTCH2 in 4 breast cancers. The p53 pathway was inactivated by mutations of TP53 in 13 breast cancers and potentially by aberrant methylation of its downstream genes in 10 breast cancers. Cell adhesion was affected by mutations of CDH1 in 1 breast cancer.
Conclusion:
Genes involved in cancer-related pathways were frequently affected not only by genetic but also by epigenetic alterations in HER2-positive breast cancer.
Insights
Genetic and epigenetic alterations frequently impact cancer pathways in HER2-positive breast cancer, contributing to trastuzumab resistance. Understanding these changes is crucial for developing new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Trastuzumab resistance is a significant challenge in treating HER2-positive breast cancer.
- Identifying underlying genetic and epigenetic alterations is key to overcoming treatment resistance.
Purpose of the Study:
- To characterize genetic and epigenetic alterations in cancer-related pathways.
- To investigate these alterations in HER2-positive breast cancer patients undergoing neoadjuvant therapy.
Main Methods:
- Analysis of 24 HER2-positive breast cancer tissue samples.
- Next-generation sequencing for genetic alterations in 409 cancer genes.
- Bead array analysis for DNA methylation status of 485,512 probes.
Main Results:
- WNT, AKT/mTOR, and Notch pathways showed activation via methylation or mutations.
- TP53 mutations and downstream gene methylation inactivated the p53 pathway in multiple cases.
- CDH1 mutations affected cell adhesion in one case.
Conclusions:
- Cancer-related genes in HER2-positive breast cancer are frequently altered by both genetic and epigenetic modifications.
- These alterations provide potential targets for overcoming trastuzumab resistance.
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