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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome
Masahiro Gotoh1, Hitoshi Ichikawa, Eri Arai
1Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
The aim of this study was to clarify the participation of expression of chimeric transcripts in renal carcinogenesis. Whole transcriptome analysis (RNA sequencing) and exploration of candidate chimeric transcripts using the deFuse program were performed on 68 specimens of cancerous tissue (T) and 11 specimens of non-cancerous renal cortex tissue (N) obtained from 68 patients with clear cell renal cell carcinomas (RCCs) in an initial cohort. As positive controls, two RCCs associated with Xp11.2 translocation were analyzed. After verification by reverse transcription (RT)-PCR and Sanger sequencing, 26 novel chimeric transcripts were identified in 17 (25%) of the 68 clear cell RCCs. Genomic breakpoints were determined in five of the chimeric transcripts. Quantitative RT-PCR analysis revealed that the mRNA expression levels for the MMACHC, PTER, EPC2, ATXN7, FHIT, KIFAP3, CPEB1, MINPP1, TEX264, FAM107A, UPF3A, CDC16, MCCC1, CPSF3, and ASAP2 genes, being partner genes involved in the chimeric transcripts in the initial cohort, were significantly reduced in 26 T samples relative to the corresponding 26 N samples in the second cohort. Moreover, the mRNA expression levels for the above partner genes in T samples were significantly correlated with tumor aggressiveness and poorer patient outcome, indicating that reduced expression of these genes may participate in malignant progression of RCCs. As is the case when their levels of expression are reduced, these partner genes also may not fully function when involved in chimeric transcripts. These data suggest that generation of chimeric transcripts may participate in renal carcinogenesis by inducing dysfunction of tumor-related genes.
Insights
Chimeric transcripts in clear cell renal cell carcinoma (RCC) are linked to reduced expression of key genes, potentially driving cancer progression and poorer patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (RCC) is a significant health concern.
- The role of chimeric transcripts in renal carcinogenesis remains unclear.
- Understanding genetic alterations in RCC is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the involvement of chimeric transcript expression in renal carcinogenesis.
- To identify novel chimeric transcripts in clear cell RCC.
- To assess the impact of chimeric transcripts on gene expression and patient outcomes.
Main Methods:
- Whole transcriptome analysis (RNA sequencing) and deFuse program for chimeric transcript identification.
- Reverse transcription (RT)-PCR and Sanger sequencing for verification.
- Quantitative RT-PCR to analyze mRNA expression levels of partner genes.
Main Results:
- 26 novel chimeric transcripts identified in 25% of clear cell RCC cases.
- Genomic breakpoints determined for five chimeric transcripts.
- Significantly reduced mRNA expression of partner genes (e.g., MMACHC, PTER, EPC2) in tumor tissues compared to normal tissues.
- Reduced expression of partner genes correlated with tumor aggressiveness and poorer patient outcomes.
Conclusions:
- Chimeric transcript generation may contribute to renal carcinogenesis.
- Reduced expression of partner genes, potentially due to involvement in chimeric transcripts, may drive malignant progression.
- Chimeric transcripts can induce dysfunction in tumor-related genes, impacting RCC development.
