title: De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer.
abstract: BACKGROUND
  MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling of circulating small RNAs has not been reported in breast cancer (BC), and was carried out in this study to identify blood-based small RNA markers of BC clinical outcome.
  
  
  METHODS
  The pre-treatment sera of 42 stage II-III locally advanced and inflammatory BC patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for marker identification by deep sequencing all circulating small RNAs. An independent validation cohort of 26 stage II-III BC patients was used to assess the power of identified miRNA markers.
  
  
  RESULTS
  More than 800 miRNA species were detected in the circulation, and observed patterns showed association with histopathological profiles of BC. Groups of circulating miRNAs differentially associated with ER/PR/HER2 status and inflammatory BC were identified. The relative levels of selected miRNAs measured by PCR showed consistency with their abundance determined by deep sequencing. Two circulating miRNAs, miR-375 and miR-122, exhibited strong correlations with clinical outcomes, including NCT response and relapse with metastatic disease. In the validation cohort, higher levels of circulating miR-122 specifically predicted metastatic recurrence in stage II-III BC patients.
  
  
  CONCLUSIONS
  Our study indicates that certain miRNAs can serve as potential blood-based biomarkers for NCT response, and that miR-122 prevalence in the circulation predicts BC metastasis in early-stage patients. These results may allow optimized chemotherapy treatments and preventive anti-metastasis interventions in future clinical applications.
authors.affiliation: Department of Cancer Biology, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, CA 91010, USA.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Palomares
authors.forename: Arthur Xuejun
authors.initials: AX
authors.lastname: Li
authors.forename: Weiying
authors.initials: W
authors.lastname: Zhou
authors.forename: Amy
authors.initials: A
authors.lastname: Chow
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.forename: Harry
authors.initials: H
authors.lastname: Gao
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.forename: Sierra
authors.initials: S
authors.lastname: Li
authors.forename: Kimlin Tam
authors.initials: KT
authors.lastname: Ashing-Giwa
authors.forename: Guihua
authors.initials: G
authors.lastname: Sun
authors.forename: Yafan
authors.initials: Y
authors.lastname: Wang
authors.forename: Robin
authors.initials: R
authors.lastname: Smith
authors.forename: Kim
authors.initials: K
authors.lastname: Robinson
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.forename: Shizhen Emily
authors.initials: SE
authors.lastname: Wang
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics*; D058977:Molecular Sequence Annotation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D012008:Recurrence; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs