Genome-wide profiling of transfer RNAs and their role as novel prognostic markers for breast cancer

Abstract

Transfer RNAs (tRNAs, key molecules in protein synthesis) have not been investigated as potential prognostic markers in breast cancer (BC), despite early findings of their dysregulation and diagnostic potential. We aim to comprehensively profile tRNAs from breast tissues and to evaluate their role as prognostic markers (Overall Survival, OS and Recurrence Free Survival, RFS). tRNAs were profiled from 11 normal breast and 104 breast tumor tissues using next generation sequencing. We adopted a Case-control (CC) and Case-Only (CO) association study designs. Risk scores constructed from tRNAs were subjected to univariate and multivariate Cox-proportional hazards regression to investigate their prognostic value. Of the 571 tRNAs profiled, 76 were differentially expressed (DE) and three were significant for OS in the CC approach. We identified an additional 11 tRNAs associated with OS and 14 tRNAs as significant for RFS in the CO approach, indicating that CC alone may not capture all discriminatory tRNAs in prognoses. In both the approaches, the risk scores were significant in the multivariate analysis as independent prognostic factors, and patients belonging to high-risk group were associated with poor prognosis. Our results confirmed global up-regulation of tRNAs in BC and identified tRNAs as potential novel prognostic markers for BC.

The dysregulation of tRNAs and tRNA derivatives in cancer

“…Using means of a new tRNA profiling method, investigators revealed that specific tRNAs, tRNA Arg CCG and tRNA Glu UUC , were upregulated in highly metastatic breast cancer cells compared to poorly metastatic counterpart due to their enhanced stability and translation of the codon-rich transcripts [ 57 ]. These up-regulated tRNAs might serve as potential novel prognostic markers in addition to their involvement in the pathogenesis of breast cancer [ 69 ].…”

Targeted sequencing reveals expanded genetic diversity of human transfer RNAs

“…Danielson et al [71] and Umu et al [72] identified 356 and 411 unique tRNAs, respectively, in plasma using RNA sequencing approaches. It is estimated that cells express between 300 and 400 tRNA genes, based on microarray [73][74][75][76] or RNA sequencing approaches [31,[77][78][79]. This number is consistent with RNA polymerase III and TFIIIC occupancy [80][81][82].…”

The Challenges and Opportunities in the Clinical Application of Noncoding RNAs: The Road Map for miRNAs and piRNAs in Cancer Diagnostics and Prognostics

“…piRNA transcripts were also observed to be generated from long noncoding RNAs which are >200 nt in length. In addition, we [ 118 , 119 ] and others [ 120 – 123 ] have suggested that transfer RNAs and small nucleolar RNAs may also be the sources of piRNAs as we observed some of the piRNA genes to exist within the boundaries of transfer RNAs and small nucleolar RNAs [ 118 – 123 ]. However, the process through which piRNA transcripts are generated remains elusive.…”