ABSTRACT
Background: The early detection of colon cancer is one of the main prerequisites for successful treatment and mortality reduction. Circulating PIWI-interacting RNAs (piRNA) were recently identified as novel promising biomarkers. The purpose of the study was to assess the profiles of piRNAs in blood serum of colon cancer patients with the aim to identify those with high diagnostic potential.Methods: Blood serum samples from 403 colon cancer patients and 276 healthy donors were included in this 3-phase biomarker study. Large-scale piRNA expression profiling was performed using Illumina small RNA sequencing. The diagnostic potential of selected piRNAs was further validated on independent training and validation sets of samples using RT-qPCR.Results: In total, 31 piRNAs were found to be significantly deregulated in serum of cancer patients compared with healthy donors. Based on the levels of piR-5937 and piR-28876, it was possible to differentiate between cancer patients and healthy donors with high sensitivity and specificity. Moreover, both piRNAs exhibited satisfactory diagnostic performance also in patients with stage I disease and enabled detection of colon cancer with higher sensitivity than currently used biomarkers CEA and CA19-9. Finally, the expression of analyzed piRNAs in blood restored significantly 1 month after the surgical resection.Conclusions: Based on our findings, piRNAs are abundant in human blood serum. Furthermore, their levels in colon cancer have been observed to be significantly deregulated. However, their involvement in carcinogenesis must be further established.Impact: piRNAs could serve as promising noninvasive biomarkers for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1019-28. ©2018 AACR.
Subject(s)
Biomarkers, Tumor/genetics , Colonic Neoplasms/diagnosis , Gene Expression Regulation, Neoplastic , RNA, Small Interfering/genetics , Aged , Case-Control Studies , Colonic Neoplasms/genetics , Female , Follow-Up Studies , Humans , Male , Middle Aged , PrognosisABSTRACT
PURPOSE: This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival. METHODS: Mutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency. Leukemia-related characteristics were additionally analyzed in an extended group of 68 samples that included the 47 de novo samples, and additional 21 samples from refractory and relapsed cases. Engraftment outcomes were compared with overall and event-free survival of the patients. RESULTS: For the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1 mut /DNMT3A mut co-mutation was associated with higher engraftment ability. NPM1 mut /FLT3-ITD neg had lower engraftment intensity. Among leukemia-related characteristics, a complex karyotype was associated with higher engraftment intensity. Among patient-related characteristics, higher cytogenetic risk was associated with higher engraftment intensity, and failure to achieve clinical remission was associated with shorter engraftment latency. In the extended group of 68 samples, white blood count was associated with higher engraftment ability, and the presence of a complex karyotype was associated with higher engraftment intensity. Association with patient overall survival was seen only for engraftment intensity. CONCLUSIONS: The engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Mutation , Adult , Aged , Animals , Heterografts/pathology , Humans , Leukemia, Myeloid, Acute/blood , Leukocytes , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Nucleophosmin , Transplantation, Heterologous , Young AdultABSTRACT
Early detection of colorectal cancer is the main prerequisite for successful treatment and reduction of mortality. Circulating microRNAs were previously identified as promising diagnostic, prognostic and predictive biomarkers. The purpose of this study was to identify serum microRNAs enabling early diagnosis and prognosis prediction of colon cancer. In total, serum samples from 427 colon cancer patients and 276 healthy donors were included in three-phase biomarker study. Large-scale microRNA expression profiling was performed using Illumina small RNA sequencing. Diagnostic and prognostic potential of identified microRNAs was validated on independent training and validation sets of samples using RT-qPCR. Fifty-four microRNAs were found to be significantly deregulated in serum of colon cancer patients compared to healthy donors (P < 0.01). A diagnostic four-microRNA signature consisting of miR-23a-3p, miR-27a-3p, miR-142-5p and miR-376c-3p was established (AUC = 0.917), distinguishing colon cancer patients from healthy donors with sensitivity of 89% and specificity of 81% (AUC = 0.922). This panel of microRNAs exhibited high diagnostic performance also when analyzed separately in colon cancer patients in early stages of the disease (T1-4N0M0; AUC = 0.877). Further, a prognostic panel based on the expression of miR-23a-3p and miR-376c-3p independent of TNM stage was established (HR 2.30; 95% CI 1.44-3.66; P < 0.0004). In summary, highly sensitive signatures of circulating microRNAs enabling non-invasive early detection and prognosis prediction of colon cancer were identified.
