ABSTRACT
Colorectal cancer (CRC) is a malignant tumor initiating from the mucosa of the colorectum. According to the 2020 statistics from the World Health Organization, there are 10.0% CRC cases among all 19.3 million new cancers, followed by lung and breast cancer, and 9.4% CRC cases among all 9.9 million cancer deaths, ranking second. The population of CRC patients in China is large, and its incidence and mortality continue to increase each year. Despite the continuous development of surgical methods, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the overall survival of CRC patients remains low. Past research has suggested that c-myc plays a pivotal role in the development of CRC. A higher expression level of c-Myc is a negative prognostic marker in CRC. However, there are few drugs targeting c-myc directly. Therefore, we focused on discovering the mechanism of c-myc in CRC to provide a reference for a better therapy choice for patients (AU)
Subject(s)
Humans , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , ChinaABSTRACT
Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
Subject(s)
Cerebellar Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Medulloblastoma/genetics , Transcriptome , Adult , Aged , Aged, 80 and over , Cerebellar Neoplasms/pathology , Child , Child, Preschool , Cluster Analysis , DNA Copy Number Variations , Female , Gene Expression Profiling/methods , Genetic Heterogeneity , Genome-Wide Association Study , Humans , INDEL Mutation , Male , Medulloblastoma/pathology , Middle Aged , Mutation , Polymorphism, Single Nucleotide , Principal Component Analysis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
Subject(s)
Cerebellar Neoplasms/therapy , Clone Cells/drug effects , Clone Cells/metabolism , Medulloblastoma/therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Selection, Genetic/drug effects , Animals , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/radiotherapy , Cerebellar Neoplasms/surgery , Clone Cells/pathology , Craniospinal Irradiation , DNA Mutational Analysis , Disease Models, Animal , Drosophila melanogaster/cytology , Drosophila melanogaster/genetics , Female , Genome, Human/genetics , Humans , Male , Medulloblastoma/genetics , Medulloblastoma/pathology , Medulloblastoma/radiotherapy , Medulloblastoma/surgery , Mice , Molecular Targeted Therapy/methods , Neoplasm Recurrence, Local/therapy , Radiotherapy, Image-Guided , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
The usefulness of a genetic clock lies in its role to stimulate a sequence of logic reactions for sequential biological circuits. A clock signal is a periodic square wave, its amplitude alternates at a steady frequency between fixed minimal and maximal levels. Transition between the minimum and the maximum is instantaneous for an ideal square wave; however, the function is unrealisable in physical bio-systems. This research develops a new genetic clock generator based on a genetic oscillator, in which, a sine wave generator is adopted as a signal oscillator. It is shown that combination of a genetic oscillator with a toggle switch is able to generate clock signals forming an efficient way to generate a near square wave. In silico study confirms the proposed idea.
