Integrated miRNA Signatures: Advancing Breast Cancer Diagnosis and Prognosis

Abstract

Breast cancer ranks first in incidence and second in deaths worldwide, presenting alarmingly rising mortality rates. Imaging methodologies and/or invasive biopsies are routinely used for screening and detection, although not always with high sensitivity/specificity. MicroRNAs (miRNAs) could serve as diagnostic and prognostic biomarkers for breast cancer. We have designed a computational approach combining transcriptome profiling, survival analyses, and diagnostic power calculations from 1165 patients with breast invasive carcinoma from The Cancer Genome Atlas (TCGA-BRCA). Our strategy yielded two separate miRNA signatures consisting of four up-regulated and five down-regulated miRNAs in breast tumors, with cumulative diagnostic strength of AUC 0.93 and 0.92, respectively. We provide direct evidence regarding the breast cancer-specific expression of both signatures through a multicancer comparison of >7000 biopsies representing 19 solid cancer types, challenging their diagnostic potency beyond any of the current diagnostic methods. Our signatures are functionally implicated in cancer-related processes with statistically significant effects on overall survival and lymph-node invasion in breast cancer patients, which underlie their strong prognostic implication. Collectively, we propose two novel miRNA signatures with significantly elevated diagnostic and prognostic power as a functionally resolved tool for binary and accurate detection of breast cancer and other tumors of the female reproductive system.