Plasma tRNA Fragments Derived from 5' Ends as Novel Diagnostic Biomarkers for Early-Stage Breast Cancer

Jingyi Wang; Ge Ma; Minghui Li; Xu Han; Jin Xu; Mengdi Liang; Xinrui Mao; Xiang Chen; Tiansong Xia; Xiaoan Liu; Shui Wang

doi:10.1016/j.omtn.2020.07.026

Plasma tRNA Fragments Derived from 5' Ends as Novel Diagnostic Biomarkers for Early-Stage Breast Cancer

Mol Ther Nucleic Acids. 2020 Sep 4:21:954-964. doi: 10.1016/j.omtn.2020.07.026. Epub 2020 Jul 23.

Authors

Jingyi Wang¹, Ge Ma¹, Minghui Li¹, Xu Han², Jin Xu³, Mengdi Liang², Xinrui Mao², Xiang Chen⁴, Tiansong Xia⁵, Xiaoan Liu⁶, Shui Wang⁷

Affiliations

¹ Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 211166 Nanjing, China.
² Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China.
³ Department of Breast and Thyroid Surgery, Nanjing First Hospital, Nanjing Medical University, 210029 Nanjing, China.
⁴ Thyroid and Breast Department, Yixing People's Hospital affiliated to Jiangsu University, 214200 Yixing, China.
⁵ Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 211166 Nanjing, China. Electronic address: xiatsswms@163.com.
⁶ Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 211166 Nanjing, China. Electronic address: liuxiaoan@126.com.
⁷ Department of Breast Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, 210029 Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 211166 Nanjing, China. Electronic address: ws0801@hotmail.com.

Abstract

Small RNAs derived from tRNAs are attracting considerable attention; however, the effects of tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs) as biomarkers have not been investigated in early-stage breast cancer (EBC). The study aimed to explore whether tRFs and tiRNAs could be detected in plasma and whether they could serve as diagnostic biomarkers. The study was conducted in four phases. Thirty tRFs and tiRNAs were selected by high-throughput sequencing in screening phase and then assessed in training, testing, and external validation phases by qRT-PCR. Six tRFs (tRF-Glu-CTC-003, tRF-Gly-CCC-007, tRF-Gly-CCC-008, tRF-Leu-CAA-003, tRF-Ser-TGA-001, and tRF-Ser-TGA-002) were found significantly downregulated in plasma samples of patients with EBC compared with normal controls, and all were derived from 5' ends of tRNAs. Patients with HER2⁺ EBC with low expression levels of tRF-Glu-CTC-003 were related to worse disease-free survival and overall survival. The identified tRFs were further examined in cell supernatants, exosomes isolated from plasma, and tissues. In conclusion, our study identified six tRFs from the 5' ends of tRNAs as novel diagnostic biomarkers for EBC, providing additional evidence for, and a better understanding of, circulating tRFs and EBC.

Keywords: biomarker; breast cancer; diagnosis; noninvasive detection; tRNA fragments.