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Serum tRNA-derived fragments (tRFs) as potential candidates for diagnosis of non-triple-negative breast cancer

ABSTRACT: Breast cancer is one of the most common cancers in the world and non-triple-negative breast cancer (non-TNBC) accounts for 80-90% of all invasive breast cancers. Early detection of breast cancer is considered as key to successful treatment. Conventionally，breast imaging and needle core biopsy are used for detection and monitoring of disease progression. However, small volume changes may be ignored on imaging and traditional biopsy is spatially and temporally limited, leading to a significant lag time in detecting cancer progression. This thus prompted renewed focus on early and accurate diagnosis. In this article, we committed to investigate whether there exists accurate molecule in peripheral blood which can help diagnose breast cancer. tRNA-derived fragments (tRFs) have been reported to be involved in many pathological processes, but whether it can serve as biomarkers for the diagnosis of breast cancer remains unclear. Using high-throughput sequencing technology, we identified 4021 differentially expressed tRFs in normal breast epithelial cell lines and non-triple-negative breast cancer cell lines and 8 tRFs were selected to construct a signature to predict the non-TNBC. Further, qRT-PCR was conducted to verify its expression and to analyze the correlation between dysregulated tRFs and breast cancer. The results indicated that tDR-7816, tDR-5334, tDR-4733 might be promising biomarkers. Through further bioinformatics analysis, we predicted that tDR-7816 influences xenobiotic metabolic process that support the oncogenesis of breast cancer. Taken together, our results provide a rationale for using circulating tDR-7816 expression as a novel potential biomarker to diagnose early non-TNBC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134992 | GEO | 2019/10/30

REPOSITORIES: GEO

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Project description:Background: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs (tDRs), a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tDRs and trastuzumab resistance is still unknown. Methods: We detected the levels of tDRs expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed tDRs in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tDRs. Progression-free survival (PFS) was analyzed using Cox-regression. Furthermore, Gene Ontology (GO) and pathway analyses indicated the potential mechanism underlying tDR-mediated trastuzumab resistance. Results: Our sequence results showed that tDRs were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tDR-1960 and tDR-1969 were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tDR-1960 and tDR-1969 were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tDR-1960 and tDR-1969 expression were associated with signiﬁcantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Additionally, the GO analysis indicated that tDR-1960 and tDR-1969 were mainly involved in the cellular response to drug, which may partially explain the molecular mechanism underlying trastuzumab resistance in HER-2 positive breast cancer. Conclusion: we comprehensively analyzed tDRs in trastuzumab-sensitive and -resistant breast cancer. Our results suggest that tDR-1960 and tDR-1969 play important roles in trastuzumab resistance. Patients with high levels of tDR-1960 and tDR-1969 expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these tDRs. tDR-1960 and tDR-1969 may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

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Serum tRNA-derived fragments (tRFs) as potential candidates for diagnosis of non-triple-negative breast cancer

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