Development and validation of a circulating microRNA panel for the early detection of breast cancer

Ruiyang Zou,Ann S G Lee,Yew Chung Tang,Sau Yeen Loke,Lihan Zhou,Heng-Phon Too,Mikael Hartman

doi:10.1038/s41416-021-01593-6

Abstract

BackgroundMammography is widely used for breast cancer screening but suffers from a high false-positive rate. Here, we perform the largest comprehensive, multi-center study to date involving diverse ethnic groups, for the identification of circulating miRNAs for breast cancer screening.MethodsThis study had a discovery phase (n = 289) and two validation phases (n = 374 and n = 379). Quantitative PCR profiling of 324 miRNAs was performed on serum samples from breast cancer (all stages) and healthy subjects to identify miRNA biomarkers. Two-fold cross-validation was used for building and optimising breast cancer-associated miRNA panels. An optimal panel was validated in cohorts with Caucasian and Asian samples. Diagnostic ability was evaluated using area under the curve (AUC) analysis.ResultsThe study identified and validated 30 miRNAs dysregulated in breast cancer. An optimised eight-miRNA panel showed consistent performance in all cohorts and was successfully validated with AUC, accuracy, sensitivity, and specificity of 0.915, 82.3%, 72.2% and 91.5%, respectively. The prediction model detected breast cancer in both Caucasian and Asian populations with AUCs ranging from 0.880 to 0.973, including pre-malignant lesions (stage 0; AUC of 0.831) and early-stage (stages I–II) cancers (AUC of 0.916).ConclusionsOur panel can potentially be used for breast cancer screening, in conjunction with mammography.

Highlights

Mammography is widely used for breast cancer screening but suffers from a high false-positive rate
Discovery and validation of significant differentially regulated miRNAs The expression levels of 324 miRNAs, which have been previously detected with high confidence in human serum, were quantified in the Discovery Cohort of 289 Caucasian samples (183 breast cancer samples and 106 non-cancer controls)
We describe here an eight-miRNA biomarker signature that can differentiate between breast cancer patients and non-cancer individuals, which was derived from a multi-ethnic study comprising of a discovery phase followed by two validation phases

Summary

Introduction

Mammography is widely used for breast cancer screening but suffers from a high false-positive rate. An optimised eight-miRNA panel showed consistent performance in all cohorts and was successfully validated with AUC, accuracy, sensitivity, and specificity of 0.915, 82.3%, 72.2% and 91.5%, respectively. Mammography has been widely-used as a screening tool for breast cancer despite its high false-positive rate, and its lack of sensitivity in detecting cancer in dense breasts [1]. A high rate of false positivity of 11–12% has been detected among women in the United States who have undergone mammographic screening [2, 3] Invasive methods such as miRNA-based liquid biopsies can potentially overcome these disadvantages and improve overall detection accuracy [4, 5]. It is known that miRNAs regulate oncogenesis through their tumour suppressor or oncogenic activities, with increasing evidence of aberrant miRNA expression in a variety of malignancies [9]

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Results

Conclusion