Abstract
One of the most abundant, yet least explored, classes of RNA is the small nucleolar RNAs (snoRNAs), which are well known for their involvement in post-transcriptional modifications of other RNAs. Although snoRNAs were only considered to perform housekeeping functions for a long time, recent studies have highlighted their importance as regulators of gene expression and as diagnostic/prognostic markers. However, the prognostic potential of these RNAs has not been interrogated for breast cancer (BC). The objective of the current study was to identify snoRNAs as prognostic markers for BC. Small RNA sequencing (Illumina Genome Analyzer IIx) was performed for 104 BC cases and 11 normal breast tissues. Partek Genomics Suite was used for analyzing the sequencing files. Two independent and proven approaches were used to identify prognostic markers: case-control (CC) and case-only (CO). For both approaches, snoRNAs significant in the permutation test, following univariate Cox proportional hazards regression model were used for constructing risk scores. Risk scores were subsequently adjusted for potential confounders in a multivariate Cox model. For both approaches, thirteen snoRNAs were associated with overall survival and/or recurrence free survival. Patients belonging to the high-risk group were associated with poor outcomes, and the risk score was significant after adjusting for confounders. Validation of representative snoRNAs (SNORD46 and SNORD89) using qRT-PCR confirmed the observations from sequencing experiments. We also observed 64 snoRNAs harboring piwi-interacting RNAs and/or microRNAs that were predicted to target genes (mRNAs) involved in tumorigenesis. Our results demonstrate the potential of snoRNAs to serve (i) as novel prognostic markers for BC and (ii) as indirect regulators of gene expression.
Highlights
Breast cancer (BC) is a complex polygenic disease [1] characterized by molecular and histological heterogeneity [2]
40 small nucleolar RNAs (snoRNAs) are differentially expressed in BC
Read distribution of representative snoRNAs are illustrated in S1 Fig. The read distributions confirm that the identified snoRNA fragments are not unique to formalin fixed paraffin embedded (FFPE) tissues, as the flash frozen (FF) normal reduction mammoplasty tissues exhibited these characteristics, negating the view that storage of the samples under different conditions would have generated the fragments
Summary
Breast cancer (BC) is a complex polygenic disease [1] characterized by molecular and histological heterogeneity [2]. The diagnostic and prognostic factors related to BC outcomes are being increasingly refined, there remains a need to improve on the specificity and sensitivity of prognostic markers which may impact the quality of life for BC patients. Optimal management of BC is challenging due to the varied treatment response patterns exhibited by patients undergoing similar treatment regimens [3,4]. The available treatment modalities might be better applied if we could stratify treatment responders from non-responders, which may eventually help in improving survival and quality of life. Progesterone and human epidermal growth factor receptors are routinely used as prognostic markers, in addition to tumor and patient related factors, these indices remain as imperfect estimators for risk of recurrence and/or death [5]. There is an ongoing search for better prognostic markers for BC
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