Transcriptome analysis reveals overlap in fusion genes in a phase I clinical cohort of TNBC and HGSOC patients treated with buparlisib and olaparib

Autor: Sheida Nabavi, Panagiotis A. Konstantinopoulos, Charles J. Murphy, Gerburg M. Wulf, Julia Eismann, Ioannis S. Vlachos, Ursula A. Matulonis, Yujing J. Heng, Kathryn P. Gray, Johannes M. Waldschmidt
Rok vydání: 2019
Předmět:
0301 basic medicine
Oncology
Cancer Research
Original Article – Clinical Oncology
Buparlisib
Aminopyridines
Triple Negative Breast Neoplasms
Fusion gene
Piperazines
Transcriptome
chemistry.chemical_compound
Breast cancer
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Medicine
RNA-Seq
Ovarian Neoplasms
MALAT1
Clinical Trials
Phase I as Topic
Forkhead Transcription Factors
General Medicine
Middle Aged
3. Good health
030220 oncology & carcinogenesis
PARP inhibitor
Female
Gene Fusion
Adult
WWOX
medicine.medical_specialty
Morpholines
Olaparib
03 medical and health sciences
Ovarian cancer
Internal medicine
Humans
Aged
business.industry
Gene Expression Profiling
Genomic profiling
medicine.disease
Cystadenocarcinoma
Serous
Repressor Proteins
030104 developmental biology
chemistry
Phthalazines
business
Zdroj: Journal of Cancer Research and Clinical Oncology
ISSN: 1432-1335
0171-5216
Popis: Purpose Fusion genes can be therapeutically relevant if they result in constitutive activation of oncogenes or repression of tumor suppressors. However, the prevalence and role of fusion genes in female cancers remain largely unexplored. Here, we investigate the fusion gene landscape in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), two subtypes of female cancers with high molecular similarity but limited treatment options at present. Methods RNA-seq was utilized to identify fusion genes in a cohort of 18 TNBC and HGSOC patients treated with the PI3K inhibitor buparlisib and the PARP inhibitor olaparib in a phase I clinical trial (NCT01623349). Differential gene expression analysis was performed to assess the function of fusion genes in silico. Finally, these findings were correlated with the reported clinical outcomes. Results A total of 156 fusion genes was detected, whereof 44/156 (28%) events occurred in more than one patient. Low recurrence across samples indicated that the majority of fusion genes were private passenger events. The long non-coding RNA MALAT1 was involved in 97/156 (62%) fusion genes, followed in prevalence by MUC16, FOXP1, WWOX and XIST. Gene expression of FOXP1 was significantly elevated in patients with vs. without FOXP1 fusion (P= 0.02). From a clinical perspective, FOXP1 fusions were associated with a favorable overall survival. Conclusions In summary, this study provides the first characterization of fusion genes in a cohort of TNBC and HGSOC patients. An improved mechanistic understanding of fusion genes will support the future identification of innovative therapeutic approaches for these challenging diseases.
Databáze: OpenAIRE
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