Circulating microRNAs in plasma as early detection markers for breast cancer

In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time‐point of diagnosis) and healthy control individuals using TaqMan low‐density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT‐qPCR. Four miRNAs (miR‐148b, miR‐376c, miR‐409‐3p and miR‐801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR‐148b, miR‐409‐3p and miR‐801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood‐based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests.

[1]  Keith W. Jones,et al.  Impact of Cellular miRNAs on Circulating miRNA Biomarker Signatures , 2011, PloS one.

[2]  R. Bast,et al.  American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[4]  Sung-Chou Li,et al.  Epigenetic regulation of miR‐34b and miR‐129 expression in gastric cancer , 2011, International journal of cancer.

[5]  E. DeLong,et al.  Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. , 1988, Biometrics.

[6]  Jean-Baptiste Cazier,et al.  Distinctive Patterns of MicroRNA Expression Associated with Karyotype in Acute Myeloid Leukaemia , 2008, PloS one.

[7]  D. Kang,et al.  Identification of Serum MicroRNAs as Novel Non-Invasive Biomarkers for Early Detection of Gastric Cancer , 2012, PloS one.

[8]  Ignace Vergote,et al.  Expression profiling of cancerous and normal breast tissues identifies microRNAs that are differentially expressed in serum from patients with (metastatic) breast cancer and healthy volunteers , 2012, Breast Cancer Research.

[9]  Heidi Dvinge,et al.  HTqPCR: high-throughput analysis and visualization of quantitative real-time PCR data in R , 2009, Bioinform..

[10]  S. Oliver Trends in prostate cancer mortality in England, Wales, and the USA. , 2000, The Lancet. Oncology.

[11]  T. Kinoshita,et al.  Long-term prognostic study of carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA 15-3) in breast cancer , 2008, International Journal of Clinical Oncology.

[12]  B. Burwinkel,et al.  Characterization of extracellular circulating microRNA , 2011, Nucleic acids research.

[13]  Brigitte Rack,et al.  Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer , 2010, Breast Cancer Research.

[14]  G. Illei,et al.  The Majority of MicroRNAs Detectable in Serum and Saliva Is Concentrated in Exosomes , 2012, PloS one.

[15]  Zheng Wang,et al.  Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  E. Kroh,et al.  Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies , 2011, Cancer Prevention Research.

[17]  A. Harris,et al.  Detection of elevated levels of tumour‐associated microRNAs in serum of patients with diffuse large B‐cell lymphoma , 2008, British journal of haematology.

[18]  Ross Ihaka,et al.  Gentleman R: R: A language for data analysis and graphics , 1996 .

[19]  Xianghuo He,et al.  MicroRNA-409 suppresses tumour cell invasion and metastasis by directly targeting radixin in gastric cancers , 2012, Oncogene.

[20]  Zhaohui Huang,et al.  Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer , 2010, International journal of cancer.

[21]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[22]  Xi Chen,et al.  Expression profile of microRNAs in serum: a fingerprint for esophageal squamous cell carcinoma. , 2010, Clinical chemistry.

[23]  Alicia Algeciras-Schimnich,et al.  Analysis of circulating microRNA: preanalytical and analytical challenges. , 2011, Clinical chemistry.

[24]  M. L. Hastings,et al.  Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells , 2010, PloS one.

[25]  Chengzhong Xing,et al.  MicroRNA‐148b suppresses cell growth by targeting cholecystokinin‐2 receptor in colorectal cancer , 2012, International journal of cancer.

[26]  Muneesh Tewari,et al.  Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). , 2010, Methods.

[27]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

[28]  F. Pépin,et al.  Stromal gene expression predicts clinical outcome in breast cancer , 2008, Nature Medicine.

[29]  George A Calin,et al.  MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. , 2008, JAMA.

[30]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Lijuan Guo,et al.  Decreased serum miR-181a is a potential new tool for breast cancer screening. , 2012, International journal of molecular medicine.

[32]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[33]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[34]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[35]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[36]  Kazuhiro Yoshida,et al.  Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. , 2010, The Lancet. Oncology.

[37]  Ulus Atasoy,et al.  Circulating microRNAs in breast cancer and healthy subjects , 2009, BMC Research Notes.

[38]  Holger Sültmann,et al.  Circulating miRNAs are correlated with tumor progression in prostate cancer , 2011, International journal of cancer.

[39]  Hua Zhao,et al.  A Pilot Study of Circulating miRNAs as Potential Biomarkers of Early Stage Breast Cancer , 2010, PloS one.

[40]  Jiyon Lee,et al.  The relationship of mammographic density and age: implications for breast cancer screening. , 2012, AJR. American journal of roentgenology.

[41]  H. Iwase,et al.  [Breast cancer]. , 2006, Nihon rinsho. Japanese journal of clinical medicine.

[42]  E. Kroh,et al.  Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma , 2011, Proceedings of the National Academy of Sciences.

[43]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[44]  E. Feuer,et al.  SEER Cancer Statistics Review, 1975-2003 , 2006 .

[45]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[46]  Harikrishna Nakshatri,et al.  Persistent upregulation of U6:SNORD44 small RNA ratio in the serum of breast cancer patients , 2011, Breast Cancer Research.