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Cancer Lett. 2018 Aug 1;428:127-138. doi: 10.1016/j.canlet.2018.04.020. Epub 2018 Apr 22.

Novel cancer gene variants and gene fusions of triple-negative breast cancers (TNBCs) reveal their molecular diversity conserved in the patient-derived xenograft (PDX) model.

Author information

1
Department of Biomedical Sciences, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea; Department of Pathology, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
2
Department of Bio and Brain Engineering, KAIST, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
3
Department of Biomedical Sciences, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
4
Department of Surgery, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
5
Department of Pathology, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.
6
Basic Research Laboratory, Stem Cell Regulation and Animal Aging Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: singhshr@mail.nih.gov.
7
Department of Biomedical Sciences, University of Ulsan School of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea. Electronic address: suhwan.chang@amc.seoul.kr.

Abstract

Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors. Genomic analysis of 10 primary tumor-PDX pairs with Ion AmpliSeq CCP revealed high degree of variant conservation (85.0%-96.9%) between primary and PDXs. Further analysis showed 44 rare variants with a predicted high impact in 36 genes including Trp53, Pten, Notch1, and Col1a1. Among them, we confirmed frequent Notch1 variant. Furthermore, RNA-seq analysis of 24 PDXs revealed 594 gene fusions, of which 163 were in-frame, including AZGP1-GJC3 and NF1-AARSD1. Finally, western blot analysis of oncogenic signaling proteins supporting molecular diversity of TNBC PDXs. Overall, our report provides a molecular basis for the usefulness of the TNBC PDX model in preclinical study.

KEYWORDS:

Cancer panel; Diversity; Gene fusion; Novel variant; Patient-derived xenografts; Triple-negative breast cancer

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