• Humans
• Neoplasms/pathology
• Neoplasms/genetics
• Biological Evolution

• 1R01CA258089 National Cancer Institute (NCI)

• cancer evolution
• causal inference
• causality
• evolutionary divergence
• prostate cancer

• P01 CA265768 NCI NIH HHS
• P50 CA211024 NCI NIH HHS
• R01 CA259200 NCI NIH HHS
• R01 CA285772 NCI NIH HHS

• Adaptation
• Cancer
• Ecosystems
• Evolutionary ecology

• Animals
• Biological Evolution
• Neoplasms/genetics
• Neoplasms/veterinary
• Carcinogenesis/genetics
• Humans
• Ecosystem
• Ecology
• Oncogenes/physiology

• cancer
• evolution

• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Mutation
• Selection, Genetic
• Biomarkers, Tumor/genetics
• Mutation, Missense
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology

• RR170048 Cancer Prevention and Research Institute of Texas
• U19CA203654 NIH HHS
• National Institutes of Health

• cancer
• computational modelling
• evolution
• evolutionary medicine
• population genetics

• U54 CA217376 NCI NIH HHS
• National Cancer Institute

• breast cancer (BC)
• eco-evo-devo theories
• onco-breastomics
• progression
• tumorigenesis

• Humans
• Female
• Ecosystem
• Breast Neoplasms
• Mastectomy
• Biological Evolution
• Developmental Biology

• R15 CA260126 NCI NIH HHS
• R15CA260126 NCI NIH HHS

• cancer genomics
• molecular evolution
• transfer learning

• U54 CA217376 NCI NIH HHS
• U54-CA217376 NIH HHS
• R01-LM013438 NIH HHS
• U2C CA233254 NCI NIH HHS
• R01-CA140657 NIH HHS
• R21-CA257980 NIH HHS
• R01 LM013438 NLM NIH HHS
• U2C-CA233254 NIH HHS
• R01 CA140657 NCI NIH HHS
• R21 CA257980 NCI NIH HHS

• Humans
• Neoplasms/genetics
• Neoplasms/prevention & control
• Oncogenes
• Mutation
• Stem Cells
• Aging

• Cancer Research UK
• P01 CA096832 NCI NIH HHS
• U54 CA243125 NCI NIH HHS

• cancer
• chimeric RNA
• drug-resistance
• precision medicine
• sense-antisense chimeric RNA

• Humans
• RNA/genetics
• Neoplasms/genetics
• Biomarkers
• Transcriptome
• RNA, Long Noncoding/genetics

• Cancer evolution
• Driver mutations
• Evolutionary patterns
• Genomics
• Natural selection
• Somatic mutations

• Grant No. 31971371 National Natural Science Foundation of China

• bioinformatics
• polyploid giant cancer cells (PGCCs)
• systems biology
• tumor evolution

• Humans
• Cell Line, Tumor
• Neoplasm Recurrence, Local/pathology
• Giant Cells/metabolism
• Giant Cells/pathology
• Polyploidy
• Computational Biology

• conditioned medium
• iTSCs
• induced tumor-suppressing cells
• proteomes

• aging
• cancer
• cancer suppression mechanisms
• development
• evolution
• somatic maintenance

• alveoli
• epithelium
• lung
• metastasis
• pneumocytes

• Epithelial Cells/pathology
• Pulmonary Alveoli/pathology
• Respiratory Mucosa
• Epithelium
• Lung/pathology

• F32 CA239436 NCI NIH HHS
• T32 CA190216 NCI NIH HHS
• American Cancer Society (ACS)
• HHS | NIH | National Cancer Institute (NCI)
• METAvivor

Clinically, early-stage oral cancers are difficult to distinguish from oral potentially malignant disorders (OPMDs) because they show a variety of mucosal pathologies. Therefore, invasive tissue biopsies should be performed to determine the treatment strategy. Previously, we focused on gargle fluid as a noninvasive testing method and reported aberrant methylation in gargle fluid in patients with oral cancer. In this study, we successfully identified aberrantly methylated genes in early-stage oral cancer and reported that a combination of methylation of six genes could distinguish early-stage oral cancer from OPMDs, with high diagnostic performance. In addition, the methylation panel more accurately reflected the presence of early-stage oral cancer than cytology testing. Our results suggest that the methylation panel using gargle fluid has the potential to be used as a noninvasive screening tool to diagnose early-stage cancer.

Clinically, early-stage oral cancers are difficult to distinguish from oral potentially malignant disorders (OPMDs), and invasive tissue biopsy should be performed to determine a treatment strategy. Previously, we focused on gargle fluid as a noninvasive testing method and reported aberrant methylation in gargle fluid in patients with oral cancer. This study aimed to distinguish early-stage oral cancer from clinically diagnosed OPMDs using gargle fluid samples. We collected gargle fluid samples from 40 patients who were clinically diagnosed with OPMDs in the training set; among them, 9 patients were pathologically diagnosed with oral cancer. Methylation levels of 25 tumor suppressor genes were analyzed using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) method. We found that a combination of six genes (TP73, CASP8, RARB, KLLN, GSTP1, and CHFR) could distinguish oral cancer from clinically diagnosed OPMDs with high diagnostic performance (area under the curve [AUC], 0.885; sensitivity, 77.8%; and specificity, 87.1%). Additionally, the panel comprised of the six methylated genes was validated in the test set. Furthermore, when compared with cytology testing, the panel could accurately detect oral cancer. The present methylated gene panel may serve as a novel biomarker for oral cancer.

• DNA methylation
• biomarker
• gargle fluid
• oral cancer
• oral potentially malignant disorders
• oral squamous carcinoma

• clonal evolution
• simulation model
• targeted therapy
• treatment outcomes
• tumor heterogeneity

Human multiforme glioblastoma is characterized by an unfavorable prognosis, low survival rate and extremely limited possibilities for therapy. Rat C6 glioma is an experimental model for the study of glioblastoma growth and invasion. It has been shown that the growth and development of the tumor is accompanied by changes in the surrounding normotypic tissues [1]. These changes create a favorable environment for the development of the tumor and give it an evolutionary advantage [2]. Description of changes occurring in normotypic cells of the body upon their contact with tumor cells is of great interest. We have grown C6 glioma cells and rat astrocytes, as well as astrocyte cells co-cultured together with C6 glioma. We performed proteome-wide LC-MS analysis of these experimental groups. The data includes LC-MS/MS raw files and exported MaxQuant and ProteinPilot search results with fasta. Dataset published in the PRIDE repository project accession PXD026776.

• Co-culture
• Glioma C6
• LC-MS/MS
• Proteome

• Abortion, Spontaneous/epidemiology
• Adolescent
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Neonatal Screening
• Neoplasms/epidemiology
• Neoplasms/genetics
• Pregnancy
• Registries
• Retrospective Studies
• Sweden/epidemiology
• Twins/statistics & numerical data

• adaptation
• cancer therapy
• cell growth
• environment
• natural selection
• stress response
• tumor evolution

• cancer genomics
• acute myeloid leukaemia
• tumour heterogeneity
• evolutionary biology

• Acute Disease
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Breast Neoplasms/drug therapy
• Clonal Evolution/drug effects
• Clonal Evolution/genetics
• Clone Cells/drug effects
• Clone Cells/metabolism
• Clone Cells/pathology
• Cohort Studies
• Female
• Fluorouracil/administration & dosage
• Fluorouracil/adverse effects
• Hematopoiesis/drug effects
• Hematopoiesis/genetics
• Humans
• Isocitrate Dehydrogenase/genetics
• Leukemia, Myeloid/chemically induced
• Leukemia, Myeloid/genetics
• Mutagenesis/drug effects
• Mutation/drug effects
• Neoplasms, Second Primary/chemically induced
• Neoplasms, Second Primary/genetics
• Platinum/administration & dosage
• Platinum/adverse effects
• Tumor Suppressor Protein p53/genetics

• biosensors
• breast cancer
• early diagnosis
• heterogeneity
• multigene assays
• novel biomarkers

• Biological Sciences
• Cancer Systems Biology
• Evolutionary Biology
• Evolutionary Ecology

• MUC16
• adoptive T-cell therapy
• checkpoint inhibition
• glycans
• immune system
• immunotherapy
• ovarian cancer
• tumour microenvironment

• N/A Ovarian Cancer Research Foundation

• cancer genomics
• cancer models

• Computational Biology
• Databases, Genetic
• Gene Expression
• Humans
• Neoplasm Staging
• Neoplasms/genetics
• Neoplasms/pathology
• Prognosis
• Software

Neoplasia is a multilevel condition caused by irregularities over the genome, which can lead to a fatal result. To fully understand this phenomenon, an evolutionary challenge has risen during the last decades, away from human limits, driving the scientific quest into the wild life. The study of wild vertebrate populations in their natural habitats has shown that cancer is rather prominent. Thus, the diversity of vertebrates reported with some form of neoplasia is quite scattered through a variety of habitats. However, some species constitute exceptions by exhibiting cancer-protective features, driven by certain loci in their DNA. It is obvious that from an evolutionary standpoint, the incidence of cancer in different taxa is nowadays studied by seeking for patterns and their roots. The main purpose of the evolutionary approach is no other than to answer a fundamental question: Could cancer be ultimately regarded as another evolutionary force conducive to the formation or shaping-up of species?

• Animal taxa
• Cancer
• Evolution
• Neoplasia
• Phenotype
• Speciation
• Vertebrates

The Hippo pathway is a central regulator of organ size and a key tumor suppressor via coordinating cell proliferation and death. Initially discovered in Drosophila, the Hippo pathway has been implicated as an evolutionarily conserved pathway in mammals; however, how this pathway was evolved to be functional from its origin is still largely unknown. In this study, we traced the Hippo pathway in premetazoan species, characterized the intrinsic functions of its ancestor components, and unveiled the evolutionary history of this key signaling pathway from its unicellular origin. In addition, we elucidated the paralogous gene history for the mammalian Hippo pathway components and characterized their cancer-derived somatic mutations from an evolutionary perspective. Taken together, our findings not only traced the conserved function of the Hippo pathway to its unicellular ancestor components, but also provided novel evolutionary insights into the Hippo pathway organization and oncogenic alteration.

• digital pathology
• image analysis
• omics
• pathology informatics
• precision medicine
• virtual slides

• Ciona intestinalis
• Intrinsically disordered proteins
• Molecular basis of disease
• Protein-RNA interactions
• RNA world
• Transcription factor
• mRNA translation

• Animals
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Humans
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Binding
• Protein Interaction Domains and Motifs
• RNA, Messenger/genetics
• RNA-Binding Proteins/metabolism
• Transcriptome
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

Progenitor-like cancer cells that can survive in reversible quiescence when faced with various challenges in the body are often behind disease progression. A lack of glutamine in culture medium, which eliminates >99.9% of proliferating SUM149 triple-negative breast cancer cells, selects such adaptable, pan-resistant cells. Our data support the hypothesis that a lack of glutamine forces the selection of an epigenetic state that does not require a high level of TET2, thus selecting an “undifferentiated” therapy-resistant phenotype as seen in TET2-mutant cancers. Our data suggesting that highly adaptable cells are generated through reprograming of the epigenome and transcriptome led us to evaluate low-dose 6-mercaptopurine as a potential therapy in our model. We found that a long treatment with low-dose 6-mercaptopurine inhibited the proliferation of these adaptable cells to a greater extent than it inhibited parental cells. Importantly, a small percentage of adaptable cells survived a low-dose 6-mercaptopurine treatment in a reversible quiescence, analogous to the persistence of abnormal progenitor-like cells in inflammatory bowel disease, which stays in a durable remission with a 6-mercaptopurine treatment. Based on a biomarkers analysis, a long treatment with 6-mercaptopurine or aspirin partially reversed epithelial to mesenchymal transition in adaptable cancer cells. A cell culture model of adaptable cancer cells that persist in the body will help in discovering superior therapies that can be offered before the disease advances to metastasis.

• TET2
• cancer evolution
• inflammatory breast cancer
• metabolic adaptability in cancer
• minimal residual disease

The exact cause of cancer is one of the most immutable medical questions of the century. Cancer as an evolutionary disease must have a purpose and understanding the purpose is more important than decoding the cause. The model of cancer proposed herein, provides a link between the cellular biochemistry and cellular genetics of cancer evolution. We thus call this model as the “Nexus model” of cancer. The Nexus model is an effort to identify the most apparent route to the disease. We have tried to utilize existing cancer literature to identify the most plausible causes of cellular transition in cancer, where the primary cancer-causing agents (physical, chemical or biological) act as inducing factors to produce cellular impeders. These cellular impeders are further linked to the Nexus. The Nexus then generates codes for epigenetics and genetics in cancer development.

• Biochemical stress
• Cancer
• Epigenetics
• Genetics
• Mutations
• The Nexus model

• Breast carcinoma
• MKT-077
• P-glycoprotein
• P-gp efflux pump
• drug resistance
• mitoautophagosomes
• mitochondria
• multidrug resistance

• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Autophagosomes/drug effects
• Autophagosomes/pathology
• Autophagosomes/ultrastructure
• Breast Neoplasms/metabolism
• Breast Neoplasms/pathology
• Breast Neoplasms/ultrastructure
• Cell Line, Tumor
• Drug Resistance, Multiple/drug effects
• Drug Resistance, Multiple/physiology
• Drug Resistance, Neoplasm/drug effects
• Drug Resistance, Neoplasm/physiology
• Female
• Humans
• Microscopy, Electron, Transmission
• Mitochondria/drug effects
• Mitochondria/pathology
• Mitochondria/ultrastructure
• Pyridines/pharmacology
• Thiazoles/pharmacology

• Z99 EY999999 Intramural NIH HHS

• Agriculture
• Head and neck
• Organochlorine
• Pesticide
• Risk factor

• Circulating tumor cells
• PD-L1
• epithelial mesenchymal transition
• lung cancer

As biosensing devices shrink smaller and smaller, they approach a scale in which single molecule electronic sensing becomes possible. Here, we review the operation of single-enzyme transistors made using single-walled carbon nanotubes. These novel hybrid devices transduce the motions and catalytic activity of a single protein into an electronic signal for real-time monitoring of the protein’s activity. Analysis of these electronic signals reveals new insights into enzyme function and proves the electronic technique to be complementary to other single-molecule methods based on fluorescence. As one example of the nanocircuit technique, we have studied the Klenow Fragment (KF) of DNA polymerase I as it catalytically processes single-stranded DNA templates. The fidelity of DNA polymerases makes them a key component in many DNA sequencing techniques, and here we demonstrate that KF nanocircuits readily resolve DNA polymerization with single-base sensitivity. Consequently, template lengths can be directly counted from electronic recordings of KF’s base-by-base activity. After measuring as few as 20 copies, the template length can be determined with <1 base pair resolution, and different template lengths can be identified and enumerated in solutions containing template mixtures.

• DNA polymerase
• DNA sequencing
• carbon nanotube sensors
• single molecule enzymology

• Biosensing Techniques
• DNA
• DNA-Directed DNA Polymerase
• Nanotechnology
• Nanotubes, Carbon
• Templates, Genetic
• Transistors, Electronic

• R01 CA133592 NCI NIH HHS
• R01 GM106957 NIGMS NIH HHS

• biomedicine
• cancer
• disease biology
• evolutionary medicine

Mutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hypermutagenesis that lead to cluster formation, we analyzed the mutational single nucleotide variations (SNV) data obtained by whole-genome sequencing of drug-resistant mutants induced in yeast diploids by AID/APOBEC deaminase and base analog 6-HAP. Deaminase from sea lamprey, PmCDA1, induced robust clusters, while 6-HAP induced a few weak ones. We found that PmCDA1, AID, and APOBEC1 deaminases preferentially mutate the beginning of the actively transcribed genes. Inactivation of transcription initiation factor Sub1 strongly reduced deaminase-induced can1 mutation frequency, but, surprisingly, did not decrease the total SNV load in genomes. However, the SNVs in the genomes of the sub1 clones were re-distributed, and the effect of mutation clustering in the regions of transcription initiation was even more pronounced. At the same time, the mutation density in the protein-coding regions was reduced, resulting in the decrease of phenotypically detected mutants. We propose that the induction of clustered mutations by deaminases involves: a) the exposure of ssDNA strands during transcription and loss of protection of ssDNA due to the depletion of ssDNA-binding proteins, such as Sub1, and b) attainment of conditions favorable for APOBEC action in subpopulation of cells, leading to enzymatic deamination within the currently expressed genes. This model is applicable to both the initial and the later stages of oncogenic transformation and explains variations in the distribution of mutations and kataegis events in different tumor cells.

Genomes of tumors are heavily enriched with mutations. Some of these mutations are distributed non-randomly, forming mutational clusters. Editing cytosine deaminases from APOBEC superfamily are responsible for the formation of many of these clusters. We have expressed APOBEC enzyme in diploid yeast cells and found that most of the mutations occur in the beginning of the active genes, where transcription starts. Clusters of mutations overlapped with promoters/transcription start sites. This is likely due to the weaker protection of ssDNA, an ultimate APOBEC deaminase enzyme target, in the beginning of the genes. This hypothesis was reinforced by the finding that inactivation of Sub1 transcription initiation factor, which is found predominantly in the regions of transcription initiation, leads to further increase in mutagenesis in the beginning of the genes. Interestingly, the total number of mutations in the genomes of Sub1-deficient clones did not change, despite the 100-fold decrease in frequency of mutants in a reporter gene. Thus, the drastic change in genome-wide distribution of mutations can be caused by inactivation of a single gene. We propose that the loss of ssDNA protection factors causes formation of mutation clusters in human cancer.

• biomedical research
• evolution of disease
• host–pathogen interactions
• human genetics
• medical practice
• mismatch hypothesis
• premedical curriculum
• public health
• science education