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

Journal of Translational Medicine

Shizhen Emily Wang⁷  Xiubao Ren²  Kim Robinson⁵  Robin Smith³  Yafan Wang⁵  Guihua Sun⁵  Kimlin Tam Ashing-Giwa³  Sierra Li⁴  Paul Frankel⁴  Yate-Ching Yuan⁶  Jinhui Wang⁶  Harry Gao⁶  John J Rossi¹  Yun Yen⁵  Amy Chow⁷  Weiying Zhou⁷  Arthur Xuejun Li⁴  Melanie R Palomares³  Yang Yu²  George Somlo⁵  Xiwei Wu⁶ 

[1] Department of Molecular and Cellular Biology, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA;Department of Immunology & Biotherapy, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, 300060, China;Department of Population Sciences, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA;Department of Biostatistics, City of Hope Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 Duarte Road, Duarte, 91010, USA;Department of Medical Oncology, City of Hope Medical Center, 1500 Duarte Road, Duarte, 91010, USA;Department of Molecular Medicine, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA;Department of Cancer Biology, City of Hope Beckman Research Institute, 1500 Duarte Road, Duarte, 91010, USA

关键词: Metastasis;    Neoadjuvant chemotherapy;    Biomarker;    miRNA;    Breast cancer;   

Others  :  1206039
DOI  :  10.1186/1479-5876-10-42

 received in 2012-01-05, accepted in 2012-03-08,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Wu et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]National Cancer Institute Surveillance Epidemiology and End Results. Cancer survival statistics [http://seer.cancer.gov/statistics/types.html#4] webcite
• [2]Guarneri V, Conte P: Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy. Oncologist 2009, 14:645-656.
• [3]Guarneri V, Frassoldati A, Giovannelli S, Borghi F, Conte P: Primary systemic therapy for operable breast cancer: a review of clinical trials and perspectives. Cancer Lett 2007, 248:175-185.
• [4]Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, et al.: Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007, 25:4414-4422.
• [5]Alm El-Din MA, Taghian AG: Breast conservation therapy for patients with locally advanced breast cancer. Semin Radiat Oncol 2009, 19:229-235.
• [6]Specht J, Gralow JR: Neoadjuvant chemotherapy for locally advanced breast cancer. Semin Radiat Oncol 2009, 19:222-228.
• [7]Nicolini A, Giardino R, Carpi A, Ferrari P, Anselmi L, Colosimo S, Conte M, Fini M, Giavaresi G, Berti P, Miccoli P: Metastatic breast cancer: an updating. Biomed Pharmacother 2006, 60:548-556.
• [8]Rubens RD: 7. Management of advanced breast cancer. Int J Clin Pract 2001, 55:676-679.
• [9]Yardley DA: Visceral disease in patients with metastatic breast cancer: efficacy and safety of treatment with ixabepilone and other chemotherapeutic agents. Clin Breast Cancer 2010, 10:64-73.
• [10]Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004, 116:281-297.
• [11]Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer 2006, 6:857-866.
• [12]Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, et al.: MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005, 65:7065-7070.
• [13]Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004, 101:2999-3004.
• [14]Fu SW, Chen L, Man YG: miRNA Biomarkers in Breast Cancer Detection and Management. J Cancer 2011, 2:116-122.
• [15]Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ, Barbosa-Morais NL, Teschendorff AE, Green AR, Ellis IO, et al.: MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol 2007, 8:R214. BioMed Central Full Text
• [16]Mattie MD, Benz CC, Bowers J, Sensinger K, Wong L, Scott GK, Fedele V, Ginzinger D, Getts R, Haqq C: Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 2006, 5:24. BioMed Central Full Text
• [17]Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, Benes V, Roche H, Dalenc F, Auboeuf D, Millevoi S, Vagner S: Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res 2009, 69:8332-8340.
• [18]Fassan M, Baffa R, Palazzo JP, Lloyd J, Crosariol M, Liu CG, Volinia S, Alder H, Rugge M, Croce CM, Rosenberg A: MicroRNA expression profiling of male breast cancer. Breast Cancer Res 2009, 11:R58. BioMed Central Full Text
• [19]Taylor DD, Gercel-Taylor C: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008, 110:13-21.
• [20]Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, et al.: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 2008, 105:10513-10518.
• [21]Asaga S, Kuo C, Nguyen T, Terpenning M, Giuliano AE, Hoon DS: Direct serum assay for microRNA-21 concentrations in early and advanced breast cancer. Clin Chem 2011, 57:84-91.
• [22]Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Newell J, Kerin MJ: Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg 2010, 251:499-505.
• [23]Pigati L, Yaddanapudi SC, Iyengar R, Kim DJ, Hearn SA, Danforth D, Hastings ML, Duelli DM: Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One 2010, 5:e13515.
• [24]Roth C, Rack B, Muller V, Janni W, Pantel K, Schwarzenbach H: Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer. Breast Cancer Res 2010, 12:R90. BioMed Central Full Text
• [25]Zhu W, Qin W, Atasoy U, Sauter ER: Circulating microRNAs in breast cancer and healthy subjects. BMC Res Notes 2009, 2:89. BioMed Central Full Text
• [26]Lodes MJ, Caraballo M, Suciu D, Munro S, Kumar A, Anderson B: Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One 2009, 4:e6229.
• [27]Zhao H, Shen J, Medico L, Wang D, Ambrosone CB, Liu S: A pilot study of circulating miRNAs as potential biomarkers of early stage breast cancer. PLoS One 2010, 5:e13735.
• [28]Weng L, Wu X, Gao H, Mu B, Li X, Wang JH, Guo C, Jin JM, Chen Z, Covarrubias M, et al.: MicroRNA profiling of clear cell renal cell carcinoma by whole-genome small RNA deep sequencing of paired frozen and formalin-fixed, paraffin-embedded tissue specimens. J Pathol 2010, 222:41-51.
• [29]Robinson MD, McCarthy DJ, Smyth GK: edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010, 26:139-140.
• [30]Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, et al.: Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005, 11:5678-5685.
• [31]Caudle AS, Gonzalez-Angulo AM, Hunt KK, Liu P, Pusztai L, Symmans WF, Kuerer HM, Mittendorf EA, Hortobagyi GN, Meric-Bernstam F: Predictors of tumor progression during neoadjuvant chemotherapy in breast cancer. J Clin Oncol 2010, 28:1821-1828.
• [32]Chin LJ, Slack FJ: A truth serum for cancer-microRNAs have major potential as cancer biomarkers. Cell Res 2008, 18:983-984.
• [33]Girard M, Jacquemin E, Munnich A, Lyonnet S, Henrion-Caude A: miR-122, a paradigm for the role of microRNAs in the liver. J Hepatol 2008, 48:648-656.
• [34]Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K: Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 2006, 99:671-678.
• [35]Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, Huang L, Li H, Tan W, Wang C, Lin D: Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog 2011, 50:136-142.
• [36]Zhang Y, Jia Y, Zheng R, Guo Y, Wang Y, Guo H, Fei M, Sun S: Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem 2010, 56:1830-1838.
• [37]Burns DM, D'Ambrogio A, Nottrott S, Richter JD: CPEB and two poly(A) polymerases control miR-122 stability and p53 mRNA translation. Nature 2011, 473:105-108.