Next generation sequencing profiling identifies miR-574-3p and miR-660-5p as potential novel prognostic markers for breast cancer
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Date
2015
Authors
Krishnan, Preethi
Ghosh, Sunita
Wang, Bo
Li, Dongping
Narasimhan, Ashok
Berendt, Richard
Graham, Kathryn
Mackey, John R.
Kovalchuk, Olga
Damaraju, Sambasivarao
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Background: Prognostication of Breast Cancer (BC) relies largely on traditional clinical factors and biomarkers such
as hormone or growth factor receptors. Due to their suboptimal specificities, it is challenging to accurately identify
the subset of patients who are likely to undergo recurrence and there remains a major need for markers of higher
utility to guide therapeutic decisions. MicroRNAs (miRNAs) are small non-coding RNAs that function as
post-transcriptional regulators of gene expression and have shown promise as potential prognostic markers in
several cancer types including BC.
Results: In our study, we sequenced miRNAs from 104 BC samples and 11 apparently healthy normal (reduction
mammoplasty) breast tissues. We used Case–control (CC) and Case-only (CO) statistical paradigm to identify
prognostic markers. Cox-proportional hazards regression model was employed and risk score analysis was
performed to identify miRNA signature independent of potential confounders. Representative miRNAs were
validated using qRT-PCR. Gene targets for prognostic miRNAs were identified using in silico predictions and
in-house BC transcriptome dataset. Gene ontology terms were identified using DAVID bioinformatics v6.7. A total of
1,423 miRNAs were captured. In the CC approach, 126 miRNAs were retained with predetermined criteria for good
read counts, from which 80 miRNAs were differentially expressed. Of these, four and two miRNAs were significant
for Overall Survival (OS) and Recurrence Free Survival (RFS), respectively. In the CO approach, from 147 miRNAs
retained after filtering, 11 and 4 miRNAs were significant for OS and RFS, respectively. In both the approaches, the
risk scores were significant after adjusting for potential confounders. The miRNAs associated with OS identified in
our cohort were validated using an external dataset from The Cancer Genome Atlas (TCGA) project. Targets for the
identified miRNAs were enriched for cell proliferation, invasion and migration.
Conclusions: The study identified twelve non-redundant miRNAs associated with OS and/or RFS. These signatures
include those that were reported by others in BC or other cancers. Importantly we report for the first time two new
candidate miRNAs (miR-574-3p and miR-660-5p) as promising prognostic markers. Independent validation of
signatures (for OS) using an external dataset from TCGA further strengthened the study findings.
Description
Sherpa Romeo green journal: open access
Keywords
microRNA , Next generation sequencing , Breast cancer , Prognostic marker , miR-574-3p , miR-660-5p , Reduction mammoplasty , Overall survival , Recurrence free survival , TCGA
Citation
Krishnan, P., Ghosh, S., Wang, B., Dongping, L., Narasimhan, A., Berendt, R. ... Damaraju, S. (2015). Next generation sequencing profiling identifies miR-574-3- and miR-660-5p as potential novel prognostic markers for breast cancer. BMC Genomics, 16, 735. doi:10.1186/s12864-015-1899-0