ABSTRACT
BACKGROUND: Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection, which can identify disease relapse ahead of radiological imaging, has shown promising performance. The objective of this study was to develop and validate OriMIRACLE S (Minimal Residual Circulating Nucleic Acid Longitudinal Detection in Solid Tumor), a highly sensitive and specific tumor-informed assay for MRD detection. METHODS: Tumor-specific somatic single nucleotide variants (SNVs) were identified via whole exome sequencing of tumor tissue and matched germline DNA. Clonal SNVs were selected using the OriSelector algorithm for patient-specific, multiplex PCR-based NGS assays in MRD detection. Plasma-free DNA from patients with gastrointestinal tumors prior to and following an operation, and during monitoring, were ultradeep sequenced. RESULTS: The detection of three positive sites was sufficient to achieve nearly 100% overall sample level sensitivity and specificity and was determined by calculating binomial probability based on customized panels containing 21 to 30 variants. A total of 127 patients with gastrointestinal tumors were enrolled in our study. Preoperatively, MRD was positive in 18 of 26 patients (69.23%). Following surgery, MRD was positive in 24 of 82 patients (29.27%). The positivity rate for MRD was 33.33% (n = 18) for gastric adenocarcinoma and 32.26% (n = 62) for colorectal cancer. Twenty (20) of 59 patients (34.48%) experienced a change in MRD status over the monitoring period. Patients 8 and 31 responded to 3 cycles of systemic therapy, after which levels for all ctDNA dropped below the detection limit. Patient 53 was an example of using MRD to predict tumor metastasis. Patient 55 showed a weak response to treatments first and respond to new systemic therapy after tumor progression. CONCLUSION: Our study identified a sensitive and specific clinical detection method for low frequency ctDNA, and explored the detection performance of this technology in gastrointestinal tumors.
Subject(s)
Carcinoma , Circulating Tumor DNA , Gastrointestinal Neoplasms , Humans , Circulating Tumor DNA/genetics , Neoplasm, Residual/genetics , Neoplasm Recurrence, Local , Gastrointestinal Neoplasms/diagnosis , Gastrointestinal Neoplasms/geneticsABSTRACT
MicroRNA-328-3p (miR-328-3p) plays a critical role in mediating the progression of multiple types of cancers. To date, no study has concentrated on the molecular mechanism of miR-328-3p in mediating stomach adenocarcinoma (STAD). In this study, it was found that miR-328-3p was downregulated in STAD, and inhibition of miR-328-3p significantly promoted the growth, migration, invasion, and stemness of STAD cells, while miR-328-3p overexpression exerted reverse effects. Through bioinformatics analysis, it was uncovered that a cluster of differentiation 44 (CD44) was upregulated in STAD and closely associated with the prognosis of STAD patients. Mechanistically, we identified CD44 as the target gene of miR-328-3p. Notably, knockdown of CD44 abolished the promoting function of miR-328-3p inhibitor in the development of STAD. Moreover, myeloid zinc finger protein 1 (MZF1) was confirmed as an upstream transcription factor for miR-328-3p, which is involved in enhancing miR-328-3p expression. In addition, the role of MZF1 downregulation in the malignant traits of STAD cells was blocked by miR-328-3p overexpression. More importantly, upregulation of miR-328-3p efficiently suppressed STAD tumor growth in vivo. Collectively, our findings illustrated that MZF1-mediated miR-328-3p acted as a cancer suppressor in STAD progression via regulation of CD44, which suggested the possibility of the MZF1/miR-328-3p/CD44 axis as a novel promising therapeutic candidate for STAD.
Subject(s)
Adenocarcinoma , MicroRNAs , Stomach Neoplasms , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Stomach Neoplasms/pathologyABSTRACT
BACKGROUND AND AIMS: Prostate cancer-associated non-coding RNA transcript-1(PCAT-1), which is a newly discovered long non-coding RNA, is up-regulated in various cancers. We conducted a meta-analysis to assess the clinicopathological and prognostic value of PCAT-1 in patients with malignant tumors. METHODS: A systematic literature search involved PubMed, Medline, Cochrane Library, Web of Science, EMBASE database, Ovid, Chinese CNKI, and the Chinese WanFang database. The role of PCAT-1 in cancers was evaluated by pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: A total of 1005 patients from nine studies were included in this meta-analysis. High expression of PCAT-1 was associated with depth of infiltration, lymph node metastasis, distant metastasis and TNM stage. However, increased PCAT-1 expression was not related to gender, tumor size and differentiation. Moreover, high PCAT-1 expression was associated with poor overall survival (OS) and disease-free survival (DFS), and the pooled results suggested that PCAT-1 expression can be an independent predictive factor for overall survival. CONCLUSION: This meta-analysis provides evidence that PCAT-1 expression is closely correlated with depth of infiltration, lymph node metastasis, distant metastasis and TNM stage, and that increased PCAT-1 expression may be a potential prognostic biomarker in human cancers. However, more large-scale studies are warranted.