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

Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challengedue tolack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify... [ view full abstract ]

Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challengedue tolack 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 implantationwas 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2negativity (with two exceptions) between the original and PDX tumors. Genomic analysis of 10 primary tumor-PDX pairswithIonAmpliSeq CCP revealed high degree of variant conservation(85.0% to 96.9%) between primary and PDXs. Further analysis showed 44 rare variants with a predicted high impact in 36 genes including Trp53, Pten, Notch1, andCol1a1. Among them, we confirmedfrequent Notch1 variant. Furthermore, RNA-seq analysisof 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.