ABSTRACT
This corrects the article DOI: 10.1038/nature22364.
ABSTRACT
The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Cell Lineage/genetics , DNA, Neoplasm/blood , DNA, Neoplasm/genetics , Evolution, Molecular , Lung Neoplasms/genetics , Neoplasm Metastasis/diagnosis , Neoplasm Recurrence, Local/diagnosis , Biopsy/methods , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Cell Tracking , Clone Cells/metabolism , Clone Cells/pathology , DNA Mutational Analysis , Disease Progression , Drug Resistance, Neoplasm/genetics , Early Detection of Cancer/methods , Humans , Limit of Detection , Lung Neoplasms/blood , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Multiplex Polymerase Chain Reaction , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Postoperative Care/methods , Reproducibility of Results , Tumor BurdenABSTRACT
The mir-34/449 family consists of six homologous miRNAs at three genomic loci. Redundancy of miR-34/449 miRNAs and their dominant expression in multiciliated epithelia suggest a functional significance in ciliogenesis. Here we report that mice deficient for all miR-34/449 miRNAs exhibited postnatal mortality, infertility and strong respiratory dysfunction caused by defective mucociliary clearance. In both mouse and Xenopus, miR-34/449-deficient multiciliated cells (MCCs) exhibited a significant decrease in cilia length and number, due to defective basal body maturation and apical docking. The effect of miR-34/449 on ciliogenesis was mediated, at least in part, by post-transcriptional repression of Cp110, a centriolar protein suppressing cilia assembly. Consistent with this, cp110 knockdown in miR-34/449-deficient MCCs restored ciliogenesis by rescuing basal body maturation and docking. Altogether, our findings elucidate conserved cellular and molecular mechanisms through which miR-34/449 regulate motile ciliogenesis.
Subject(s)
Calmodulin-Binding Proteins/deficiency , Calmodulin-Binding Proteins/genetics , Cilia/genetics , Cilia/physiology , MicroRNAs/genetics , Morphogenesis/genetics , Animals , Animals, Newborn , Basal Bodies/metabolism , Basal Bodies/pathology , Basal Bodies/ultrastructure , Base Sequence , Calmodulin-Binding Proteins/metabolism , Centrioles/metabolism , Cilia/pathology , Cilia/ultrastructure , Epidermis/embryology , Epidermis/pathology , Female , Infertility/genetics , Infertility/physiopathology , Kartagener Syndrome/genetics , Kartagener Syndrome/pathology , Kartagener Syndrome/physiopathology , Male , Mice , Mice, Knockout , MicroRNAs/metabolism , Phenotype , Respiratory System/pathology , Respiratory System/physiopathology , Survival Analysis , Xenopus laevis/embryologyABSTRACT
As a global transcription factor, Myc regulates both protein-coding genes and noncoding microRNA genes. Myc-activated or repressed miRNAs are involved in various pathways to affect tumorigenesis, mediate apoptosis, proliferation, angiogenesis, metastasis, and metabolism downstream of Myc. Functional characterization of miRNAs in the Myc network requires the accurate detection and quantification of miRNA expression levels. Here, we describe two widely used methodologies to determine miRNA expression, including miRNA real-time PCR and miRNA northern analysis.