Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy
Abstract Background Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX)...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-020-02607-2 |
| _version_ | 1831542048626311168 |
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| author | Seongyeong Kim Dongjin Shin Ahrum Min Minjung Kim Deukchae Na Han-Byeol Lee Han Suk Ryu Yaewon Yang Go-Un Woo Kyung-Hun Lee Dae-Won Lee Tae-Yong Kim Charles Lee Seock-Ah Im Jong-Il Kim |
| author_facet | Seongyeong Kim Dongjin Shin Ahrum Min Minjung Kim Deukchae Na Han-Byeol Lee Han Suk Ryu Yaewon Yang Go-Un Woo Kyung-Hun Lee Dae-Won Lee Tae-Yong Kim Charles Lee Seock-Ah Im Jong-Il Kim |
| author_sort | Seongyeong Kim |
| collection | DOAJ |
| description | Abstract Background Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research. Methods Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model. Results Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient’s tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model. Conclusions Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes. |
| first_indexed | 2024-12-17T00:27:19Z |
| format | Article |
| id | doaj.art-aa2b06f509624680a456b231af5cf87d |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-17T00:27:19Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-aa2b06f509624680a456b231af5cf87d2022-12-21T22:10:25ZengBMCJournal of Translational Medicine1479-58762021-01-0119111710.1186/s12967-020-02607-2Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsySeongyeong Kim0Dongjin Shin1Ahrum Min2Minjung Kim3Deukchae Na4Han-Byeol Lee5Han Suk Ryu6Yaewon Yang7Go-Un Woo8Kyung-Hun Lee9Dae-Won Lee10Tae-Yong Kim11Charles Lee12Seock-Ah Im13Jong-Il Kim14Cancer Research Institute, Seoul National UniversityDepartment of Biomedical Sciences, Seoul National University College of MedicineCancer Research Institute, Seoul National UniversityMedical Research Center, Genomic Medicine Institute (GMI), Seoul National UniversityEwha Institute of Convergence Medicine, Ewha Womans University Mokdong HospitalDepartment of General Surgery, Seoul National University HospitalDepartment of Pathology, Seoul National University HospitalCancer Research Institute, Seoul National UniversityDepartment of Internal Medicine, Seoul National University Hospital, Seoul National University College of MedicineCancer Research Institute, Seoul National UniversityDepartment of Internal Medicine, Seoul National University Hospital, Seoul National University College of MedicineCancer Research Institute, Seoul National UniversityDepartment of Life Science, Ewha Womans UniversityCancer Research Institute, Seoul National UniversityCancer Research Institute, Seoul National UniversityAbstract Background Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research. Methods Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model. Results Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient’s tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model. Conclusions Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes.https://doi.org/10.1186/s12967-020-02607-2Metastatic breast cancerPatient-derived xenograftWhole-exome sequencing |
| spellingShingle | Seongyeong Kim Dongjin Shin Ahrum Min Minjung Kim Deukchae Na Han-Byeol Lee Han Suk Ryu Yaewon Yang Go-Un Woo Kyung-Hun Lee Dae-Won Lee Tae-Yong Kim Charles Lee Seock-Ah Im Jong-Il Kim Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy Journal of Translational Medicine Metastatic breast cancer Patient-derived xenograft Whole-exome sequencing |
| title | Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy |
| title_full | Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy |
| title_fullStr | Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy |
| title_full_unstemmed | Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy |
| title_short | Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy |
| title_sort | genomic profile of metastatic breast cancer patient derived xenografts established using percutaneous biopsy |
| topic | Metastatic breast cancer Patient-derived xenograft Whole-exome sequencing |
| url | https://doi.org/10.1186/s12967-020-02607-2 |
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