Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression
| Autor: | Robert L. Grossman, April Peterson, Kevin P. White, Chaitanya Bandlamudi, Vanessa Montoya, Thomas Stricker, Megan E. McNerney, Christopher D. Brown, Ralf Kittler |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research RNA splicing Microarrays Estrogen receptor Gene Expression Triple Negative Breast Neoplasms Biochemistry Cohort Studies Gene expression Breast Tumors Medicine and Health Sciences Protein Isoforms Small interfering RNAs 3' Untranslated Regions Genetics (clinical) Regulation of gene expression Genetics Aged 80 and over Genomics Middle Aged Prognosis 3. Good health Nucleic acids Gene Expression Regulation Neoplastic Bioassays and Physiological Analysis Oncology MCF-7 Cells Female Transcriptome Analysis Research Article Gene isoform Adult lcsh:QH426-470 Breast Neoplasms Biology Research and Analysis Methods 03 medical and health sciences Breast cancer Breast Cancer medicine Humans RNA Messenger Non-coding RNA Molecular Biology Ecology Evolution Behavior and Systematics Aged Genome Human Sequence Analysis RNA Gene Expression Profiling Alternative splicing Estrogen Receptor alpha Cancers and Neoplasms Biology and Life Sciences Computational Biology medicine.disease Genome Analysis Gene regulation Gene expression profiling lcsh:Genetics Alternative Splicing 030104 developmental biology RNA processing RNA |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 13, Iss 3, p e1006589 (2017) |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological behaviors, but also have distinct gene expression profiles. However, it has not been rigorously explored whether particular transcriptional isoforms are also differentially expressed among breast cancer subtypes, or whether transcript isoforms from the same sets of genes can be used to differentiate subtypes. To address these questions, we analyzed the patterns of transcript isoform expression using a small set of RNA-sequencing data for eleven Estrogen Receptor positive (ER+) subtype and fourteen triple negative (TN) subtype tumors. We identified specific sets of isoforms that distinguish these tumor subtypes with higher fidelity than standard mRNA expression profiles. We found that alternate promoter usage, alternative splicing, and alternate 3’UTR usage are differentially regulated in breast cancer subtypes. Profiling of isoform expression in a second, independent cohort of 68 tumors confirmed that expression of splice isoforms differentiates breast cancer subtypes. Furthermore, analysis of RNAseq data from 594 cases from the TCGA cohort confirmed the ability of isoform usage to distinguish breast cancer subtypes. Also using our expression data, we identified several RNA processing factors that were differentially expressed between tumor subtypes and/or regulated by estrogen receptor, including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2. RNAi knock-down of these RNA processing factors in MCF7 cells altered isoform expression. These results indicate that global dysregulation of splicing in breast cancer occurs in a subtype-specific and reproducible manner and is driven by specific differentially expressed RNA processing factors. Author summary Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease. Different subtypes of breast cancer display very different expression programs, and these expression programs are associated with different patient outcomes and with different treatment protocols. However, little is known about what drives these subtype differences. By sequencing RNA in a discovery cohort of breast cancer patients, we demonstrate that different subtypes of breast cancer can be distinguished by simply using differential transcript isoform expression. We confirmed our findings using two additional patient cohorts. We also demonstrate that differential expression of RNA processing factors between subtypes can affect differences in isoform usage. Using RNAi we knock down differentially expressed RNA processing factors including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2, and show that this knock-down results in differential isoform expression of the genes identified in our disease subtype panel. Taken together, our results indicate that global dysregulation of splicing occurs in a subtype-specific and reproducible manner in breast cancer, and is driven by specific differentially expressed RNA processing factors. |
| Databáze: | OpenAIRE |
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