Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases
Abstract Background Colorectal liver metastases (CRLM) are the leading cause of colorectal cancer (CRC)-related mortality. Transfer RNA-derived fragments (tRFs), a novel class of small non-coding RNAs (sncRNA), regulate gene expression, stress response, and immune functions in cancer. While increasi...
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BMC
2025-07-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06850-3 |
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| author | Rebecca Zirnbauer Daphni Ammon Annalena Renner Noam Hartman Polina Kalinina Patrick Starlinger Stefan Stremitzer Christoph Schwarz Klaus Kaczirek Michael Bergmann Dietmar Pils Johannes Laengle |
| author_facet | Rebecca Zirnbauer Daphni Ammon Annalena Renner Noam Hartman Polina Kalinina Patrick Starlinger Stefan Stremitzer Christoph Schwarz Klaus Kaczirek Michael Bergmann Dietmar Pils Johannes Laengle |
| author_sort | Rebecca Zirnbauer |
| collection | DOAJ |
| description | Abstract Background Colorectal liver metastases (CRLM) are the leading cause of colorectal cancer (CRC)-related mortality. Transfer RNA-derived fragments (tRFs), a novel class of small non-coding RNAs (sncRNA), regulate gene expression, stress response, and immune functions in cancer. While increasingly implicated in CRC progression, their prognostic significance in CRLM remains unknown. This study investigates the abundance and prognostic value of genomic (ge) and mitochondrial (mt) tRFs in CRLM. Methods Tumor samples from CRLM patients who underwent curative liver resection between January 2012 and December 2015 were retrospectively analyzed. Small RNA sequencing (sRNA-seq) quantified ge- and mt-tRF expression in tumor tissue. Event-free survival (EFS) was the primary outcome. Associations between tRF expression and EFS were evaluated using Cox regression, spline modeling, and network analysis. Results Among 588 screened samples, 40 met eligibility criteria (18 females [45%], median age 64 [42–79]). A total of 432 tRFs were identified, with ge-tRFs (67%) more abundant than mt-tRFs (33%). Spline regressions classified tRFs into ten prognostic groups. High ge-tRF abundance was predominantly associated with unfavorable EFS (FDR < 0.2; 94%), while mt-tRFs were significantly (p < 0.001; χ2 test) more often linked to favorable EFS (FDR < 0.2; 26%). Network analysis of tRF abundance correlations revealed higher intra-mitochondrial network density compared to the intra-genomic tRF network. No significant structural differences were observed between prognostically significant vs. non-significant or favorable vs. unfavorable tRFs. Key tRF candidates, including tRHalve3-His-CAU and tRNAleader-Gln-UUG (mt-tRFs), as well as tRFmisc-Tyr-GTA (ge-tRF), remained independent prognostic markers after adjusting for clinical covariates. Conclusion This study provides the first comprehensive characterization of tRF expression in CRLM, identifying distinct prognostic roles for ge- and mt-tRFs. While ge-tRFs correlated with poor prognosis, several mt-tRFs were linked to favorable outcomes, highlighting their potential as novel prognostic biomarkers and therapeutic targets. Graphical Abstract |
| format | Article |
| id | doaj-art-b100320e101e4235bb5cc4a42721f16a |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-b100320e101e4235bb5cc4a42721f16a2025-08-20T03:46:27ZengBMCJournal of Translational Medicine1479-58762025-07-0123111410.1186/s12967-025-06850-3Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastasesRebecca Zirnbauer0Daphni Ammon1Annalena Renner2Noam Hartman3Polina Kalinina4Patrick Starlinger5Stefan Stremitzer6Christoph Schwarz7Klaus Kaczirek8Michael Bergmann9Dietmar Pils10Johannes Laengle11Division of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDepartment of Pathology, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaDivision of Visceral Surgery, Department of General Surgery, Comprehensive Cancer Center Vienna, Medical University of ViennaAbstract Background Colorectal liver metastases (CRLM) are the leading cause of colorectal cancer (CRC)-related mortality. Transfer RNA-derived fragments (tRFs), a novel class of small non-coding RNAs (sncRNA), regulate gene expression, stress response, and immune functions in cancer. While increasingly implicated in CRC progression, their prognostic significance in CRLM remains unknown. This study investigates the abundance and prognostic value of genomic (ge) and mitochondrial (mt) tRFs in CRLM. Methods Tumor samples from CRLM patients who underwent curative liver resection between January 2012 and December 2015 were retrospectively analyzed. Small RNA sequencing (sRNA-seq) quantified ge- and mt-tRF expression in tumor tissue. Event-free survival (EFS) was the primary outcome. Associations between tRF expression and EFS were evaluated using Cox regression, spline modeling, and network analysis. Results Among 588 screened samples, 40 met eligibility criteria (18 females [45%], median age 64 [42–79]). A total of 432 tRFs were identified, with ge-tRFs (67%) more abundant than mt-tRFs (33%). Spline regressions classified tRFs into ten prognostic groups. High ge-tRF abundance was predominantly associated with unfavorable EFS (FDR < 0.2; 94%), while mt-tRFs were significantly (p < 0.001; χ2 test) more often linked to favorable EFS (FDR < 0.2; 26%). Network analysis of tRF abundance correlations revealed higher intra-mitochondrial network density compared to the intra-genomic tRF network. No significant structural differences were observed between prognostically significant vs. non-significant or favorable vs. unfavorable tRFs. Key tRF candidates, including tRHalve3-His-CAU and tRNAleader-Gln-UUG (mt-tRFs), as well as tRFmisc-Tyr-GTA (ge-tRF), remained independent prognostic markers after adjusting for clinical covariates. Conclusion This study provides the first comprehensive characterization of tRF expression in CRLM, identifying distinct prognostic roles for ge- and mt-tRFs. While ge-tRFs correlated with poor prognosis, several mt-tRFs were linked to favorable outcomes, highlighting their potential as novel prognostic biomarkers and therapeutic targets. Graphical Abstracthttps://doi.org/10.1186/s12967-025-06850-3Colorectal liver metastases, CRLMSmall RNA sequencing, sRNA-SeqtRNA-derived fragments, tRFsMitochondrial tRNA-derived fragments, mt-tRFsGenomic tRNA-derived fragments, ge-tRFs |
| spellingShingle | Rebecca Zirnbauer Daphni Ammon Annalena Renner Noam Hartman Polina Kalinina Patrick Starlinger Stefan Stremitzer Christoph Schwarz Klaus Kaczirek Michael Bergmann Dietmar Pils Johannes Laengle Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases Journal of Translational Medicine Colorectal liver metastases, CRLM Small RNA sequencing, sRNA-Seq tRNA-derived fragments, tRFs Mitochondrial tRNA-derived fragments, mt-tRFs Genomic tRNA-derived fragments, ge-tRFs |
| title | Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases |
| title_full | Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases |
| title_fullStr | Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases |
| title_full_unstemmed | Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases |
| title_short | Differential prognostic roles and clinical implications of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases |
| title_sort | differential prognostic roles and clinical implications of mitochondrial and genomic trna derived fragments in colorectal liver metastases |
| topic | Colorectal liver metastases, CRLM Small RNA sequencing, sRNA-Seq tRNA-derived fragments, tRFs Mitochondrial tRNA-derived fragments, mt-tRFs Genomic tRNA-derived fragments, ge-tRFs |
| url | https://doi.org/10.1186/s12967-025-06850-3 |
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