Browse
Submit Data
Databases
API
Help

Dataset Information

5 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Assessing the contribution of tumor mutational phenotypes to cancer progression risk.

ABSTRACT: Cancer occurs via an accumulation of somatic genomic alterations in a process of clonal evolution. There has been intensive study of potential causal mutations driving cancer development and progression. However, much recent evidence suggests that tumor evolution is normally driven by a variety of mechanisms of somatic hypermutability, which act in different combinations or degrees in different cancers. These variations in mutability phenotypes are predictive of progression outcomes independent of the specific mutations they have produced to date. Here we explore the question of how and to what degree these differences in mutational phenotypes act in a cancer to predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational phenotypes, followed by a machine learning framework to identify key features predictive of progression. Analyses of breast invasive carcinoma and lung carcinoma demonstrate that a large fraction of the risk of future clinical outcomes of cancer progression-overall survival and disease-free survival-can be explained solely from mutational phenotype features derived from the phylogenetic analysis. We further show that mutational phenotypes have additional predictive power even after accounting for traditional clinical and driver gene-centric genomic predictors of progression. These results confirm the importance of mutational phenotypes in contributing to cancer progression risk and suggest strategies for enhancing the predictive power of conventional clinical data or driver-centric biomarkers.

SUBMITTER: Tao Y

PROVIDER: S-EPMC7990181 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Assessing the potential of mutational strategies to elicit new phenotypes in industrial strains.

Project description:Industrial strains have been traditionally improved by rational approaches and combinatorial methods involving mutagenesis and selection. Recently, other methods have emerged, such as the use of artificial transcription factors and engineering of the native ones. As methods for generating genetic diversity continue to proliferate, the need for quantifying phenotypic diversity and, hence, assessing the potential of various genetic libraries for strain improvement becomes more pronounced. Here, we present a metric based on the quantification of phenotypic diversity, using Lactobacillus plantarum as a model organism. We found that phenotypic diversity can be introduced by mutagenesis of the principal sigma factor, that this diversity can be modulated by tuning the sequence diversity, and that this method compares favorably with commonly used protocols for chemical mutagenesis. The results of the diversity metric here developed also correlated well with the probability of finding improved mutants in the different libraries, as determined by recursive screening under stress. In addition, we subjected our libraries to lactic and inorganic acids and found strains with improved growth in both conditions, with a concomitant increase in lactate productivity.

| S-EPMC2268134 | biostudies-literature

Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer.

Project description:Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell-based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.

| S-EPMC9424903 | biostudies-literature

MicroRNAs Regulate Metabolic Phenotypes During Multicellular Tumor Spheroids Progression.

Project description:During tumor progression, cancer cells rewire their metabolism to face their bioenergetic demands. In recent years, microRNAs (miRNAs) have emerged as regulatory elements that inhibit the translation and stability of crucial mRNAs, some of them causing direct metabolic alterations in cancer. In this study, we investigated the relationship between miRNAs and their targets mRNAs that control metabolism, and how this fine-tuned regulation is diversified depending on the tumor stage. To do so, we implemented a paired analysis of RNA-seq and small RNA-seq in a breast cancer cell line (MCF7). The cell line was cultured in multicellular tumor spheroid (MCTS) and monoculture conditions. For MCTS, we selected two-time points during their development to recapitulate a proliferative and quiescent stage and contrast their miRNA and mRNA expression patterns associated with metabolism. As a result, we identified a set of new direct putative regulatory interactions between miRNAs and metabolic mRNAs representative for proliferative and quiescent stages. Notably, our study allows us to suggest that miR-3143 regulates the carbon metabolism by targeting hexokinase-2. Also, we found that the overexpression of several miRNAs could directly overturn the expression of mRNAs that control glycerophospholipid and N-Glycan metabolism. While this set of miRNAs downregulates their expression in the quiescent stage, the same set is upregulated in proliferative stages. This last finding suggests an additional metabolic switch of the above mentioned metabolic pathways between the quiescent and proliferative stages. Our results contribute to a better understanding of how miRNAs modulate the metabolic landscape in breast cancer MCTS, which eventually will help to design new strategies to mitigate cancer phenotype.

| S-EPMC7793838 | biostudies-literature

<i>PUF60/AURKA</i> Axis Contributes to Tumor Progression and Malignant Phenotypes in Bladder Cancer.

Project description:Abnormal expression or mutation of RNA splicing proteins are widely observed in human cancers. Here, we identified poly(U) binding splicing factor 60 (PUF60) as one of the most differentially expressed genes out of 97 RNA splicing proteins between normal and bladder cancer tissues by bioinformatics analysis of TCGA bladder cancer expression data. The expression of PUF60 was significantly higher in tumor tissues, while high PUF60 expression was associated with malignant phenotypes of bladder cancer and shorter survival time. Moreover, we identified aurora kinase A (AURKA) as a new downstream target of PUF60 in bladder cancer cells. PUF60 knockdown significantly inhibited cell viability and colony formation capacity in bladder cancer cells, whereas AURKA overexpression reversed this inhibition effect. Overexpression of PUF60 significantly promoted cell viability and colony formation in bladder cancer cells, while treatment with AURKA specific inhibitor reversed this promotive effect. Mechanistically, PUF60 specifically bound to the AURKA promoter, thereby activating its transcription and expression. Furthermore, we showed that there was a significant positive correlation between PUF60 and AURKA expression in bladder cancer tissues, and PUF60 and AURKA expression contributed to tumor progression and malignant phenotypes in the patients with bladder cancer. Collectively, these results indicate that the PUF60/AURKA axis plays a key role in regulating tumorigenesis and progression of bladder cancer, and may be a potential prognostic biomarker and therapeutic target for bladder cancer patients.

| S-EPMC7576680 | biostudies-literature

Assessing the Cumulative Contribution of New and Established Common Genetic Risk Factors to Early-Onset Prostate Cancer.

Project description:BackgroundWe assessed the evidence for association between 23 recently reported prostate cancer variants and early-onset prostate cancer and the aggregate value of 63 prostate cancer variants for predicting early-onset disease using 931 unrelated men diagnosed with prostate cancer prior to age 56 years and 1,126 male controls.MethodsLogistic regression models were used to test the evidence for association between the 23 new variants and early-onset prostate cancer. Weighted and unweighted sums of total risk alleles across these 23 variants and 40 established variants were constructed. Weights were based on previously reported effect size estimates. Receiver operating characteristic curves and forest plots, using defined cut-points, were constructed to assess the predictive value of the burden of risk alleles on early-onset disease.ResultsTen of the 23 new variants demonstrated evidence (P < 0.05) for association with early-onset prostate cancer, including four that were significant after multiple test correction. The aggregate burden of risk alleles across the 63 variants was predictive of early-onset prostate cancer (AUC = 0.71 using weighted sums), especially in men with a high burden of total risk alleles.ConclusionsA high burden of risk alleles is strongly associated with early-onset prostate cancer.ImpactOur results provide the first formal replication for several of these 23 new variants and demonstrate that a high burden of common-variant risk alleles is a major risk factor for early-onset prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(5); 766-72. ©2015 AACR.

| S-EPMC4873425 | biostudies-literature

MicroRNAs regulate metabolic phenotypes during Multicellular Tumor Spheroids progression

2020-11-11 | E-MTAB-9741 | biostudies-arrayexpress

Contribution of galectin-1, a glycan-binding protein, to gastrointestinal tumor progression.

Project description:Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1 (Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.

| S-EPMC5550776 | biostudies-other

The Contribution of Race to Breast Tumor Microenvironment Composition and Disease Progression.

Project description:Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality.

| S-EPMC7344193 | biostudies-literature

Race, tumor location, and disease progression among low-risk prostate cancer patients.

Project description:BackgroundThe relationship between race, prostate tumor location, and BCR-free survival is inconclusive. This study examined the independent and joint roles of patient race and tumor location on biochemical recurrence-free (BCR) survival.MethodsA retrospective cohort study was conducted among men with newly diagnosed, biopsy-confirmed, NCCN-defined low risk CaP who underwent radical prostatectomy (RP) at the Walter Reed National Military Medical Center from 1996 to 2008. BCR-free survival was modeled using Kaplan-Meier estimation curves and multivariable Cox proportional hazards (PH) analyses.ResultsThere were 539 eligible patients with low-risk CaP (25% African American, AA; 75% Caucasian American, CA). Median age at CaP diagnosis and post-RP follow-up time was 59.2 and 8.1 years, respectively. Kaplan-Meier analyses showed no significant association between race (P = .52) or predominant tumor location (P = .98) on BCR-free survival. In Cox PH multivariable analysis, neither race (HR = 1.18; 95% CI = 0.68-2.02; P = .56) nor predominant tumor location (HR = 1.13; 95% CI = 0.59-2.15; P = .71) was an independent predictor of BCR-free survival.ConclusionsNeither race nor predominant tumor location was associated with adverse oncologic outcome.

| S-EPMC7064097 | biostudies-literature

Contribution of epithelial-mesenchymal transition to pancreatic cancer progression.

Project description:Pancreatic adenocarcinoma (PDAC) is one of the most lethal human malignancies, with median survival of less than one year and overall five-year survival of less than 5%. There is increasing evidence demonstrating that epithelial-mesenchymal transition (EMT) contributes to pancreatic cancer metastasis and to treatment resistance. In this review, we will examine the data demonstrating the role and regulation of EMT in pancreatic cancer progression, focusing particularly on the transcription factors and microRNAs involved in EMT. We will examine how EMT is involved in the generation and maintenance of stem cells, and the role of EMT in modulating resistance of PDAC cells to drug therapies. We will also identify putative EMT-targeting agents that may help to reduce the morbidity and mortality associated with pancreatic cancer.

| S-EPMC3840442 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data