Recurrent read-through fusion transcripts in breast cancer
Autor: | Marie K. Kirby, Jason Gertz, Amy S. Nesmith, William E. Grizzle, Nicholas S. Davis, Patsy G. Oliver, Kevin M. Bowling, Katherine E. Varley, Albert F. LoBuglio, Richard M. Myers, Brian S. Roberts, Andres Forero, Donald J. Buchsbaum |
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Jazyk: | angličtina |
Předmět: |
Cancer Research
Oncogene Proteins Fusion Transcription Genetic Oncogene Proteins Molecular Sequence Data Gene Expression Estrogen receptor Breast Neoplasms Biology Bioinformatics Fusion gene Preclinical Study Breast cancer Chimeric RNA Cell Line Tumor medicine Humans skin and connective tissue diseases Triple-negative breast cancer Cell Proliferation Base Sequence Gene Expression Profiling medicine.disease Fusion protein 3. Good health Alternative Splicing Fusion transcript Oncology Genetic Loci Cancer research Female |
Zdroj: | Breast Cancer Research and Treatment |
ISSN: | 0167-6806 |
DOI: | 10.1007/s10549-014-3019-2 |
Popis: | Read-through fusion transcripts that result from the splicing of two adjacent genes in the same coding orientation are a recently discovered type of chimeric RNA. We sought to determine if read-through fusion transcripts exist in breast cancer. We performed paired-end RNA-seq of 168 breast samples, including 28 breast cancer cell lines, 42 triple negative breast cancer primary tumors, 42 estrogen receptor positive (ER+) breast cancer primary tumors, and 56 non-malignant breast tissue samples. We analyzed the sequencing data to identify breast cancer associated read-through fusion transcripts. We discovered two recurrent read-through fusion transcripts that were identified in breast cancer cell lines, confirmed across breast cancer primary tumors, and were not detected in normal tissues (SCNN1A-TNFRSF1A and CTSD-IFITM10). Both fusion transcripts use canonical splice sites to join the last splice donor of the 5′ gene to the first splice acceptor of the 3′ gene, creating an in-frame fusion transcript. Western blots indicated that the fusion transcripts are translated into fusion proteins in breast cancer cells. Custom small interfering RNAs targeting the CTSD-IFITM10 fusion junction reduced expression of the fusion transcript and reduced breast cancer cell proliferation. Read-through fusion transcripts between adjacent genes with different biochemical functions represent a new type of recurrent molecular defect in breast cancer that warrant further investigation as potential biomarkers and therapeutic targets. Both breast cancer associated fusion transcripts identified in this study involve membrane proteins (SCNN1A-TNFRSF1A and CTSD-IFITM10), which raises the possibility that they could be breast cancer-specific cell surface markers. Electronic supplementary material The online version of this article (doi:10.1007/s10549-014-3019-2) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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