Biology subjects

Cui, X.

Publications and source records attributed to Cui, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2020

MiRNA-223 Inhibits MouseGallstone Formation by Targeting Key Transporters in Hepatobiliary Cholesterol Secretion Pathway

BackgroudMiRNA-223 has previously been reported to play an essential role in hepatic cholesterol homeostasis by suppressing cholesterol synthesis, attenuating cholesterol uptake by hepatocyte from and promoting cholesterol efflux into the blood. However, its role in regulation of biliary cholesterol secretion and gallstone formation remains unknown. MethodsMice with conventional knockout (KO), hepatocyte-specific knockout ({Delta}Hepa) / knockdown (KD) or gain expression of miRNA-223 were included in the study and were subjected to lithogenic diet (LD) for various weeks. The gallbladders were harvested and subjected to cholesterol crystal imaging and gallstone mass measurement. Liver tissues were collected for western blotting, RT-qPCR, and immunohistochemistry staining. Levels of cholesterol, bile salt, phospholipids, and triglyceride were determined in serum, liver tissues, and bile by enzyme color reactive assays. 3 UTR reporter gene assays were used to verify the direct target genes for miRNA-223. ResultsLD-induced gallstone formation was remarkably accelerated in miRNA-223 KO, {Delta}Hepa, and KD mice with concurrent enhancement in total cholesterol levels in liver tissue and bile. Key biliary cholesterol transporters ABCG5 and ABCG8 were identified as direct targets of miRNA-223. Reversely, AAV-mediated hepatocyte-specific miRNA-223 overexpression prevented gallstone progression with reduced targets protein expression. ConclusionThe present study demonstrates a novel role of miRNA-223 in the regulation of hepatic bile cholesterol secretion pathway and gallstone formation by targeting ABCG5 and ABCG8 expression. Therefore, elevating miRNA-223 would be a potentially novel approach to overcome the sternness of cholesterol gallstone disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/344580v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1c418bforg.highwire.dtl.DTLVardef@134e20dorg.highwire.dtl.DTLVardef@e4e0d2org.highwire.dtl.DTLVardef@641b40_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2020

Curcumin promotes progression of AApoAII amyloidosis and peroxisome proliferation in mice by activating the PPARα signaling pathway

Curcumin is a polyphenol compound that exhibits multiple physiological activities. To elucidate the mechanisms by which curcumin affects systemic amyloidosis, we investigated amyloid deposition and molecular changes in a mouse model of amyloid apolipoprotein A-II (AApoAII) amyloidosis, in which mice were fed a curcumin-supplemented diet. Curcumin supplementation for 12 weeks significantly increased AApoAII amyloid deposition relative to controls, especially in the liver and spleen. Liver weights and plasma ApoA-II and high-density lipoprotein concentrations were significantly elevated in curcumin-supplemented groups. RNA-sequence analysis revealed that curcumin intake affected hepatic lipid metabolism via the peroxisome proliferator-activated receptor (PPAR) pathway, especially PPAR activation, resulting in increased Apoa2 mRNA expression. The increase in liver weights was due to activation of PPAR and peroxisome proliferation. Taken together, these results demonstrate that curcumin is a PPAR activator and may affect expression levels of proteins involved in amyloid deposition to influence amyloidosis and metabolism in a complex manner.

molecular biology↗

bioRxiv2020

DNN-DTIs: improved drug-target interactions prediction using XGBoost feature selection and deep neural network

Research, analysis, and prediction of drug-target interactions (DTIs) play an important role in understanding drug mechanisms, drug repositioning and design. Machine learning (ML)-based methods for DTIs prediction can mitigate the shortcomings of time-consuming and labor-intensive experimental approaches, providing new ideas and insights for drug design. We propose a novel pipeline for predicting drug-target interactions, called DNN-DTIs. First, the target information is characterized by pseudo-amino acid composition, pseudo position-specific scoring matrix, conjoint triad, composition, transition and distribution, Moreau-Broto autocorrelation, and structure feature. Then, the drug compounds are encoded using substructure fingerprint. Next, we utilize XGBoost to determine nonredundant and important feature subset, then the optimized and balanced sample vectors could be obtained through SMOTE. Finally, a DTIs predictor, DNN-DTIs, is developed based on deep neural network (DNN) via layer-by-layer learning. Experimental results indicate that DNN-DTIs achieves outstanding performance than other predictors with the ACC values of 98.78%, 98.60%, 97.98%, 98.24% and 98.00% on Enzyme, Ion Channels (IC), GPCR, Nuclear Receptors (NR) and Kuang's dataset. Therefore, DNN-DTIs's accurate prediction performance on Network1 and Network2 make it logical choice for contributing to the study of DTIs, especially, the drug repositioning and new usage of old drugs.

bioinformatics↗

bioRxiv2020

Epigenetic Interaction between UTX and DNMT1 Regulates Diet-Induced Myogenic Remodeling in Brown Fat

Brown adipocytes share the same developmental origin with skeletal muscle. Here we find that a brown adipocyte-to-myocyte remodeling also exists in mature brown adipocytes, and is induced by prolonged high fat diet (HFD) feeding, leading to brown fat dysfunction. This process is regulated by the interaction of epigenetic pathways involving histone and DNA methylation. In mature brown adipocytes, the histone demethylase UTX maintains persistent demethylation of the repressive mark H3K27me3 at Prdm16 promoter, leading to high Prdm16 expression. PRDM16 then recruits DNA methyltransferase DNMT1 to Myod1 promoter, causing Myod1 promoter hypermethylation and suppressing its expression. The interaction between PRDM16 and DNMT1 coordinately serves to maintain brown adipocyte identity while repressing myogenic remodeling in mature brown adipocytes, thus promoting their active brown adipocyte thermogenic function. Suppressing this interaction by HFD feeding induces brown adipocyte-to-myocyte remodeling, which limits brown adipocyte thermogenic capacity and compromises diet-induced thermogenesis, leading to the development of obesity.

physiology↗

bioRxiv2020

Repopulating Kupffer Cells Originate Directly from Hematopoietic Stem Cells

Kupffer cells (KCs) originate from yolk sac progenitors before birth. Throughout adulthood, they self-maintain independently from the input of circulating monocytes (MOs) at stead state, and are replenished within 2 weeks after having been depleted, but the origin of repopulating KCs in adult remains unclear. The current paradigm dictates that repopulating KCs originate from preexisting KCs or monocytes, but there remains a lack of fate-mapping evidence. In current study, we firstly traced the fate of preexisting KCs and that of monocytic cells with tissue-resident macrophage-specific and monocytic cell-specific fate mapping mouse models, respectively, and found no evidences that repopulating KCs originate from preexisting KCs or MOs. Secondly, we performed genetic lineage tracing to determine the type of progenitor cells involved in response to KC depletion in mice, and found that in response to KC depletion, hematopoietic stem cells (HSCs) proliferated in the bone marrow, mobilized into the blood, adoptively transferred into the liver and differentiated into KCs. Finally, we traced the fate of HSCs in a HSC-specific fate-mapping mouse model, in context of chronic liver inflammation induced by repeated carbon tetrachloride treatment, and confirmed that repopulating KCs originated directly from HSCs. Taken together, these findings provided strong in vivo fate-mapping evidences that repopulating KCs originate directly from Hematopoietic stem cells not from preexisting KCs or from MOs. SignificanceThere is a standing controversy in the field regarding the cellular origin of repopulating macrophages. This paper provides strong in vivo fate-mapping evidences that repopulating KCs originate directly from hematopoietic stem cells not from preexisting KCs or from MOs, which presenting a completely novel understanding of the cellular origin of repopulating Kupffer Cells and shedding light on the divergent roles of KCs in liver homeostasis and diseases.

cell biology↗

bioRxiv2020

Length of Mucin-Like Domains Enhance Cell-Ebola Virus Adhesion by Increasing Binding Probability

The Ebola virus (EBOV) hijacks normal physiological processes by apoptotic mimicry in order to be taken up by the cell it infects. The initial adhesion of the virus to the cell is based on the interaction between T-cell immunoglobulin and mucin domain protein, TIM, on the cell-surface and phosphatidylserine (PS) on the viral outer surface. Therefore, it is important to understand the interaction between EBOV/PS and TIM, with selective blocking of the interaction as a potential therapy. Recent experimental studies have shown that for TIM-dependent EBOV entry, a Mucin-like Domain (MLD) with a length of at least 120 amino acids is required, possibly due to the increase of area of the PS-coated surface sampled. We examine this hypothesis by modeling the process of TIM-PS adhesion using a coarse-grained molecular model. We find that the strength of bound PS−TIM pairs is essentially independent of TIM length. TIMs with longer MLDs have higher average binding strengths because of an increase in the probability of binding between EBOV and TIM proteins. Similarly, we find that for larger persistence length (less flexible) the average binding force decreases, again because of a reduction in the probability of binding.Statement of Significance This work studies the mechanism of TIM-dependent adhesion of the Ebola virus to a cell. Through coarse grained modeling we show that longer TIM stalks adhere more easily as they can sample a larger area, thus offering a mechanistic interpretation of an experimental finding. Better mechanistic understanding can lead to therapeutic ideas for blocking adhesion.View Full Text

biophysics↗

bioRxiv2020

Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

Neurofunctional mechanisms underlying audiovisual integration of characters and pinyin in Chinese children

Effortless print-sound integration is essential to reading development, and the superior temporal cortex (STC) is the most critical brain region. However, to date, the conclusion is almost restricted to alphabetic orthographies. To examine the neural basis in non-alphabetic languages and its relationship with reading abilities, we conducted a functional magnetic resonance imaging study in typically developing Chinese children. Two neuroimaging-based indicators of audiovisual processing--additive enhancement (higher activation in the congruent than the average activation of unimodal conditions) and neural integration (different activations between the congruent versus incongruent conditions)--were used to investigate character-sounds (opaque) and pinyin-sounds (transparent) processing. We found additive enhancement in bilateral STCs processing both character and pinyin stimulations. Moreover, the neural integrations in the left STC for the two scripts were strongly correlated. In terms of differentiation, first, areas beyond the STCs showed additive enhancement in processing pinyin-sounds. Second, while the bilateral STCs, left inferior/middle frontal and parietal regions manifested a striking neural integration (incongruent > congruent) for character-sounds, no significant clusters were revealed for pinyin-sounds. Finally, the neural integration in the left middle frontal gyrus for characters was specifically associated with silent reading comprehension proficiency, indicating automatic semantic processing during implicit character-sound integration. In contrast, the neural integration in the left STC for pinyin was specifically associated with oral reading fluency that relies on grapho-phonological mapping. To summarize, this study revealed both script-universal and script-specific neurofunctional substrates of print-sound integration as well as their processing- and region-dependent associations with reading abilities in typical Chinese children. HighlightsO_LIThe bilateral superior temporal cortices display additive enhancement in processing print-sound information regardless of orthographies. C_LIO_LIThe location, direction, and strength of the neural audiovisual integration are modulated by orthographic transparency. C_LIO_LIThe neural integration in the left middle frontal gyrus in processing character-sounds is correlated to reading comprehension. C_LIO_LIThe neural integration in the left superior temporal gyrus for pinyin is correlated with oral reading fluency. C_LIO_LIThe neural integrations of character-sounds and pinyin-sounds show spatial overlap and inter-subject correlation in the left superior temporal cortex. C_LI

neuroscience↗

bioRxiv2020

Mendelian randomization analysis revealed causal effects from gut microbiota to abdominal obesity

Although recent studies have revealed the association between the gut microbiota and obesity, the causality remains elusive. We performed a Mendelian Randomization (MR) analysis to determine whether there is a causal relationship between gut microbiota and abdominal obesity. We used a two-sample MR approach to assess the causal effect from gut microbiota to obesity based on genome-wide association studies (GWAS) summary statistics. The GWAS summary statistics of gut microbiota obtained from UK-twins cohort (N=1,126) were used as discovery sample exposure, and the GWAS summary statistics from the Genetic Environmental Microbial (GEM) project (N=1,098) were used as replication sample exposure. Trunk fat mass (TFM) summary statistics from the UK Biobank (UKB) cohort (N=330,762) were used as outcome. Bacteria were grouped into taxa features at family level. A total of 16 families were analyzed in the discovery sample. Family Barnesiellaceae was associated with TFM at the nominal significance level (b=-3.81x10-4, P=1.96x10-3). The causal association was successfully replicated in the replication sample (b=-7.34x10-3, P =2.77x10-2). Our findings provided evidence of causal relationship from microbiota to fat development, and may be helpful in selecting potential causal bacteria for manipulating candidate gut microbiota to therapy obesity. IMPORTANCEObesity, as a global public health problem, is one of the most important risk factors contributing to the overall global burden of disease, and is associated with an increased risk of cardiovascular disease, type 2 diabetes, and certain cancers. Recent studies have shown that gut microbiota is closely related to the development of obesity, but the causal relationship is unclear. Therefore, it is necessary to identify the causality between gut microbiota and obesity. The significance of our research is in identifying the causal relationship from specific bacteria to fat development, which will provide the new insights into the microbiota mediated the fat development mechanism.

genomics↗

bioRxiv2020

One-step RNA extraction for RT-qPCR detection of 2019-nCoV

The global outbreak of coronavirus disease 2019 (COVID-19) has placed an unprecedented burden on healthcare systems as the virus spread from the initial 27 reported cases in the city of Wuhan, China to a global pandemic in under three month[1]. Resources essential to monitoring virus transmission have been challenged with a demand for expanded surveillance. The CDC 2019-nCoV Real-Time Diagnostic Panel uses a real-time reverse transcription polymerase chain reaction (RT-PCR) consisting of two TaqMan probe and primer sets specific for the 2019-nCoV N gene, which codes for the nucleocapsid structural protein that encapsulates viral RNA, for the qualitative detection of 2019-nCoV viral RNA in respiratory samples. To isolate RNA from respiratory samples, the CDC lists RNA extraction kits from four manufacturers. In anticipation of a limited supply chain of RNA extraction kits and the need for test scalability, we sought to identify alternative RNA extraction methods. Here we show that direct lysis of respiratory samples can be used in place of RNA extraction kits to run the CDC 2019-nCoV Real-Time Diagnostic assay with the additional benefits of higher throughput, lower cost, faster turnaround and possibly higher sensitivity and improved safety.

molecular biology↗

bioRxiv2020

Menthol in Electronic Cigarettes: A Contributor to Respiratory Disease?

Menthol is widely used in tobacco products. This study compared the effects of menthol on human bronchial epithelium using submerged cultures, a VITROCELL(R) cloud chamber that provides air liquid interface (ALI) exposure without solvents or heating, and a Cultex ALI system that delivers aerosol equivalent to that inhaled during vaping. In submerged culture, menthol significantly increased calcium influx and mitochondrial reactive oxygen species (ROS) via the TRPM8 receptor, responses that were inhibited by a TRPM8 antagonist. VITROCELL(R) cloud chamber exposure of BEAS-2B monolayers increased mitochondrial protein oxidation, expression of the antioxidant enzyme SOD2, activation of NF-{kappa}B, and secretion of inflammatory cytokines (IL-6 and IL-8). Proteomics data collected following ALI exposure of 3D EpiAirway tissue in the Cultex showed upregulation of NRF-2-mediated oxidative stress, oxidative phosphorylation, and IL-8 signaling. Across the three platforms, menthol adversely effected human bronchial epithelium in a manner that could lead to respiratory disease. O_FIG O_LINKSMALLFIG WIDTH=115 HEIGHT=200 SRC="FIGDIR/small/988006v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@b86c96org.highwire.dtl.DTLVardef@1e12bd2org.highwire.dtl.DTLVardef@4008corg.highwire.dtl.DTLVardef@c01cad_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. Mechanism of action of menthol on human bronchial epithelium.Three in vitro platforms were used to study the effect of menthol on bronchial epithelium. In submerged culture (using BEAS-2B cells), menthol produced rapid calcium influx followed by an increase in oxidative stress and inflammatory cytokines. ALI exposure of BEAS-2B cells to unheated menthol in a cloud chamber caused activation of an inflammatory transcription factor (NF-{kappa}B) and oxidative stress. Proteomics analysis of human EpiAirway tissues exposed at the ALI to heated menthol EC aerosols identified changes in the expression of proteins involved in oxidative stress and in an inflammatory response. C_FIG

cell biology↗

bioRxiv2020

Somatic cell-derived BMPs induce male germ cell meiosis initiation during embryonic stage via regulating Dazl expression

Germ cell fate is believed to be determined by the signaling from sexually differentiated somatic cell. However, the molecular mechanism remains elusive. In this study, ectopic initiation of meiosis in male germ cells was observed during embryonic stage by over-activating CTNNB1 in Sertoli cells. Somatic cell transcriptome and single germ cell RNA-seq analysis indicated that TGF-{beta} signaling was activated after CTNNB1 over-activation. In vitro and in vivo experiments confirmed somatic cell-derived BMPs played crucial roles in germ cell meiosis initiation. Further studies revealed that Dazl was significantly increased in germ cells of CTNNB1 over-activated testes and induced by BMP signaling. DNMT3a and DNA methylation was also reduced in germ cells of CTNNB1 over-activated testes and increased by BMP signaling inhibitor treatment. Taken together, this study demonstrates that germ cell fate could be reprogrammed after sex determination. BMP signaling pathway is involved in germ cell meiosis initiation via up-regulating Dazl expression.

developmental biology↗

bioRxiv2020

Cellular heterogeneity-adjusted clonal methylation (CHALM) provides better prediction of gene expression

Promoter DNA methylation is a well-established mechanism of transcription repression, but its global correlation with gene expression is surprisingly weak. This weak correlation is due in part to the failure of current methylation quantification methods to consider the heterogeneity among sequenced bulk cells. Here, we introduce Cell Heterogeneity-Adjusted cLonal Methylation (CHALM) as a novel methylation quantification method. CHALM better explains the functional consequences of DNA methylation, such as its correlations with gene expression and H3K4me3. When applied to different methylation datasets, the CHALM method has uniquely detected differentially methylated genes that exhibit distinct biological functions supporting underlying mechanisms.

bioinformatics↗

bioRxiv2020

3D Epigenomic Characterization Reveals Insights Into Gene Regulation and Lineage Specification During Corticogenesis

Lineage-specific epigenomic changes during human corticogenesis have previously remained elusive due to challenges with tissue heterogeneity and sample availability. Here, we analyze cis-regulatory chromatin interactions, open chromatin regions, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational human brain samples. We show that chromatin looping underlies transcriptional regulation for lineage-specific genes, with transcription factor motifs, families of transposable elements, and disease-associated variants enriched at distal interacting regions in a cell type-specific manner. A subset of promoters exhibit unusually high degrees of chromatin interactivity, which we term super interactive promoters. Super interactive promoters are enriched for critical lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of cell type-specific transcription. Finally, we present CRISPRview, a novel approach for validating distal interacting regions in primary cells. Our study presents the first characterization of cell type-specific 3D epigenomic landscapes during human corticogenesis, advancing our understanding of gene regulation and lineage specification during human brain development.

genomics↗

bioRxiv2020

The transmembrane serine protease inhibitors are potential antiviral drugs for 2019-nCoV targeting the insertion sequence-induced viral infectivity enhancement

At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China1, even more spread than SARS-CoV infection2. The entry of SARS-CoV into host cells mainly depends on the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion3,4. The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear5,6. Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.

microbiology↗

bioRxiv2020

The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes

Since December 2019, a newly identified coronavirus (2019 novel coronavirus, 2019-nCov) is causing outbreak of pneumonia in one of largest cities, Wuhan, in Hubei province of China and has draw significant public health attention. The same as severe acute respiratory syndrome coronavirus (SARS-CoV), 2019-nCov enters into host cells via cell receptor angiotensin converting enzyme II (ACE2). In order to dissect the ACE2-expressing cell composition and proportion and explore a potential route of the 2019-nCov infection in digestive system infection, 4 datasets with single-cell transcriptomes of lung, esophagus, gastric, ileum and colon were analyzed. The data showed that ACE2 was not only highly expressed in the lung AT2 cells, esophagus upper and stratified epithelial cells but also in absorptive enterocytes from ileum and colon. These results indicated along with respiratory systems, digestive system is a potential routes for 2019-nCov infection. In conclusion, this study has provided the bioinformatics evidence of the potential route for infection of 2019-nCov in digestive system along with respiratory tract and may have significant impact for our healthy policy setting regards to prevention of 2019-nCoV infection.

microbiology↗

bioRxiv2019

PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa

Retinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. In this study, we demonstrate that a metabolic reprogramming can treat degeneration in a Pde6{beta} preclinical model of RP. Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that transfers phosphate from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), promoting glucose catabolism. Ablation of PKM2 resulted in enhanced photoreceptor survival and function in Pde6{beta}-mutated mice compared with those without ablation. Electroretinogram (ERG) analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with Pkm2 intact. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.

genetics↗

bioRxiv2019

Improving personalized prediction of cancer prognoses with clonal evolution models

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, known as mutator phenotypes, which act in different combinations or degrees in different cancers. Here we explore the question of how and to which degree different mutator phenotypes act in a cancer predict its future progression. We develop a computational paradigm using evolutionary tree inference (tumor phylogeny) algorithms to derive features quantifying single-tumor mutational preferences, followed by a machine learning frame-work to identify key features predictive of progression. We build phylogenies tracing the evolution of subclones of cells in tumor tissues using a variety of somatic genomic alterations, including single nucleotide variations, copy number alterations, and structural variations. We demonstrate that mutation preference features derived from the phylogenies are predictive of clinical outcomes of cancer progression - overall survival and disease-free survival - based on the analyses on breast invasive carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma. We further show that mutational phenotypes have predictive power even after accounting for traditional clinical and driver-centric predictors of progression. These results confirm the power of mutational phenotypes as an independent class of predictive biomarkers and suggest a strategy for enhancing the predictive power of conventional clinical or driver-centric genomic features.

cancer biology↗