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

Preethi Krishnan,Olga Kovalchuk,Sambasivarao Damaraju,John R Mackey,Sunita Ghosh,Bo Wang,Mieke Heyns,Dongping Li

doi:10.1038/srep32843

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.

Highlights

The discovery that only 2% of the human genome encodes for proteins and that the remaining 98% harbor sequences with structural, regulatory and functional relevance, dispelled the long-held belief that these sequences should be considered as “junk DNA”1
Maute et al, have identified a functionally active Transfer RNAs (tRNAs) derived microRNA that represses the expression of protein coding gene by means of sequence complementarity to mRNAs13. tRNAs may act as a source for another molecule called piwi-interacting RNAs17, which are considered as master regulators of gene expression[18,19]
8,247,022 reads were mappable to tRNAs, which accounted to a total of 571 tRNAs across the genome

Summary

Introduction

The discovery that only 2% of the human genome encodes for proteins (the coding portion) and that the remaining 98% (the non-coding portion) harbor sequences with structural, regulatory and functional relevance, dispelled the long-held belief that these sequences should be considered as “junk DNA”1. Amongst the non-coding portion of the genome which gets transcribed but not translated, two major classes of RNA exist based on size: long non-coding RNAs (>200 nt) and small non-coding RNAs (sncRNAs

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