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Differential prognostic roles of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases: A retrospective cohort study

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 tRFs are 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: This single-center retrospective cohort study included all CRLM patients who underwent curative liver resection between January 2012 and December 2015. Small RNA sequencing (sRNA-seq) quantified ge- and mt-tRF expression in tumor samples. Event-free survival (EFS) was the primary outcome, and the impact of tRFs on EFS was assessed using Cox regression, spline modeling of the effects of tRFs on EFS, 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%) being more abundant than mt-tRFs (33%). Using spline regressions, tRFs were classified into 10 ten prognostic groups. High ge-tRF abundance correlated predominantly with unfavorable EFS (FDR<0.2; 94%), whereas mt-tRFs were significantly (p<0.001; χ2 test) more often associated with favorable EFS (FDR<0.2; 26%). Network analysis of tRF abundance correlations revealed a significantly higher intra-mitochondrial network density compared to the intra-genomic tRF network. However, no significant differences in network structure were observed between prognostically significant vs. non-significant or favorable vs. unfavorable tRFs. Finally, key tRF candidates, such as tRHalve3-His-CAU (mt-tRF) or tRNAleader-Gln-UUG (mt-tRF) paired with tRFmisc-Tyr-GTA (ge-tRF), remained independent prognostic markers after adjustment for clinical covariates. Conclusion: This study provides the first comprehensive characterization of tRF expression in CRLM, revealing distinct prognostic roles for ge- and mt-tRFs. While ge-tRFs were predominantly associated with unfavorable prognosis, a subset of mt-tRFs demonstrated a favorable impact on EFS. These findings highlight the potential of tRFs as novel prognostic biomarkers and therapeutic targets in CRLM, warranting validation in prospective studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293849 | GEO | 2025/07/16

REPOSITORIES: GEO

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Project description:Background: As couples struggle with infertility and livestock producers wish to rapidly improve genetic merit in their herd, assisted reproductive technologies (ART) have become increasingly popular in human medicine as well as the livestock industry. Utilizing ART can cause an increased risk of congenital overgrowth syndromes, such as Large Offspring Syndrome (LOS) in ruminants. A dysregulation of transcripts has been observed in bovine fetuses with LOS, which is suggested to be a cause of the phenotype. Our recent study identified variations in tRNA expression in LOS individuals, leading us to hypothesize that variations in tRNA expression can influence the availability of their processed regulatory products, tRNA-derived fragments (tRFs). Due to their resemblance in size to microRNAs, studies suggest that tRFs target mRNA transcripts and regulate gene expression. Thus, we have sequenced small RNA isolated from skeletal muscle and liver of day 105 bovine fetuses to elucidate the mechanisms contributing to LOS. Moreover, we have utilized our previously generated tRNA sequencing data to analyze the contribution of tRNA availability to tRF abundance. Results: 22,289 and 7,737 unique tRFs were predicted in the liver and muscle tissue respectively. The greatest number of reads originated from 5′ tRFs in muscle and 5′ halves in liver. In addition, mitochondrial (MT) and nuclear derived tRF expression was tissue-specific with most MT-tRFs and nuclear tRFs derived from LysUUU and iMetCAU in muscle, and AsnGUU and GlyGCC in liver. Despite variation in tRF abundance within treatment groups, we identified differentially expressed (DE) tRFs across Control-AI, ART-Normal, and ART-LOS groups with the most DE tRFs between ART-Normal and ART-LOS groups. Many DE tRFs target transcripts enriched in pathways related to growth and development in the muscle and tumor development in the liver. Finally, we found positive correlation coefficients between tRNA availability and tRF expression in muscle (R = 0.47) and liver (0.6). Conclusion: Our results highlight the dysregulation of tRF expression and its regulatory roles in LOS. These tRFs were found to target both imprinted and non-imprinted genes in muscle as well as genes linked to tumor development in the liver. Furthermore, we found that tRNA transcription is a highly modulated event that plays a part in the biogenesis of tRFs. This study is the first to investigate the relationship between tRNA and tRF expression in combination with ART-induced LOS.

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Differential prognostic roles of mitochondrial and genomic tRNA-derived fragments in colorectal liver metastases: A retrospective cohort study

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