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De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer

Xiwei Wu2, George Somlo3, Yang Yu17, Melanie R Palomares34, Arthur Xuejun Li6, Weiying Zhou1, Amy Chow1, Yun Yen3, John J Rossi5, Harry Gao2, Jinhui Wang2, Yate-Ching Yuan2, Paul Frankel6, Sierra Li6, Kimlin Tam Ashing-Giwa4, Guihua Sun3, Yafan Wang3, Robin Smith4, Kim Robinson3, Xiubao Ren7 and Shizhen Emily Wang1*

Author Affiliations

1 Department of Cancer Biology, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA

2 Department of Molecular Medicine, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA

3 Department of Medical Oncology, City of Hope Medical Center, 1500 Duarte Road, Duarte, 91010, USA

4 Department of Population Sciences, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA

5 Department of Molecular and Cellular Biology, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA

6 Department of Biostatistics, City of Hope Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 Duarte Road, Duarte, 91010, USA

7 Department of Immunology & Biotherapy, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, 300060, China

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Journal of Translational Medicine 2012, 10:42  doi:10.1186/1479-5876-10-42

Published: 8 March 2012

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.

Keywords:
Breast cancer; miRNA; Biomarker; Neoadjuvant chemotherapy; Metastasis