ABSTRACT
To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Proteogenomics , Female , Humans , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/genetics , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/geneticsABSTRACT
Regulatory T (Treg) cells require (interleukin-2) IL-2 for their homeostasis by affecting their proliferation, survival and activation. Here we investigated transcriptional and epigenetic changes after acute, periodic and persistent IL-2 receptor (IL-2R) signaling in mouse peripheral Treg cells in vivo using IL-2 or the long-acting IL-2-based biologic mouse IL-2-CD25. We show that initially IL-2R-dependent STAT5 transcription factor-dependent pathways enhanced gene activation, chromatin accessibility and metabolic reprogramming to support Treg cell proliferation. Unexpectedly, at peak proliferation, less accessible chromatin prevailed and was associated with Treg cell contraction. Restimulation of IL-2R signaling after contraction activated signature IL-2-dependent genes and others associated with effector Treg cells, whereas genes associated with signal transduction were downregulated to somewhat temper expansion. Thus, IL-2R-dependent Treg cell homeostasis depends in part on a shift from more accessible chromatin and expansion to less accessible chromatin and contraction. Mouse IL-2-CD25 supported greater expansion and a more extensive transcriptional state than IL-2 in Treg cells, consistent with greater efficacy to control autoimmunity.
Subject(s)
Chromatin Assembly and Disassembly , Interleukin-2 , T-Lymphocytes, Regulatory , Animals , Chromatin/metabolism , Interleukin-2/metabolism , Mice , Receptors, Interleukin-2/genetics , Receptors, Interleukin-2/metabolism , Signal TransductionABSTRACT
Building Single Sample Predictors (SSPs) from gene expression profiles presents challenges, notably due to the lack of calibration across diverse gene expression measurement technologies. However, recent research indicates the viability of classifying phenotypes based on the order of expression of multiple genes. Existing SSP methods often rely on Top Scoring Pairs (TSP), which are platform-independent and easy to interpret through the concept of "relative expression reversals". Nevertheless, TSP methods face limitations in classifying complex patterns involving comparisons of more than two gene expressions. To overcome these constraints, we introduce a novel approach that extends TSP rules by constructing rank-based trees capable of encompassing extensive gene-gene comparisons. This method is bolstered by incorporating two ensemble strategies, boosting and random forest, to mitigate the risk of overfitting. Our implementation of ensemble rank-based trees employs boosting with LogitBoost cost and random forests, addressing both binary and multi-class classification problems. In a comparative analysis across 12 cancer gene expression datasets, our proposed methods demonstrate superior performance over both the k-TSP classifier and nearest template prediction methods. We have further refined our approach to facilitate variable selection and the generation of clear, precise decision rules from rank-based trees, enhancing interpretability. The cumulative evidence from our research underscores the significant potential of ensemble rank-based trees in advancing disease classification via gene expression data, offering a robust, interpretable, and scalable solution. Our software is available at https://CRAN.R-project.org/package=ranktreeEnsemble .
Subject(s)
Neoplasms , Transcriptome , Humans , Software , Neoplasms/genetics , Oncogenes , AlgorithmsABSTRACT
Epigenome-wide association studies often detect many differentially methylated sites, and many are located in distal regulatory regions. To further prioritize these significant sites, there is a critical need to better understand the functional impact of CpG methylation. Recent studies demonstrated that CpG methylation-dependent transcriptional regulation is a widespread phenomenon. Here, we present MethReg, an R/Bioconductor package that analyzes matched DNA methylation and gene expression data, along with external transcription factor (TF) binding information, to evaluate, prioritize and annotate CpG sites with high regulatory potential. At these CpG sites, TF-target gene associations are often only present in a subset of samples with high (or low) methylation levels, so they can be missed by analyses that use all samples. Using colorectal cancer and Alzheimer's disease datasets, we show MethReg significantly enhances our understanding of the regulatory roles of DNA methylation in complex diseases.
Subject(s)
DNA Methylation , Epigenesis, Genetic , CpG Islands/genetics , DNA Methylation/genetics , Genome-Wide Association Study , Transcription, GeneticABSTRACT
Identifying patients with stage II and III colon cancer who will benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy is crucial for the advancement of personalized cancer therapy. We employ a semi-supervised machine learning approach to analyze a large dataset with 933 stage II and III colon cancer samples. Our analysis leverages gene regulatory networks to discover an 18-gene prognostic signature and to explore a 10-gene signature that potentially predicts chemotherapy benefits. The 10-gene signature demonstrates strong prognostic power and shows promising potential to predict chemotherapy benefits. We establish a robust clinical assay on the NanoString nCounter platform, validated in a retrospective formalin-fixed paraffin-embedded (FFPE) cohort, which represents an important step toward clinical application. Our study lays the groundwork for improving adjuvant chemotherapy and potentially expanding into immunotherapy decision-making in colon cancer. Future prospective studies are needed to validate and establish the clinical utility of the 10-gene signature in clinical settings.
ABSTRACT
Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledgebase containing manually curated summary statistics from 98 published tables in 38 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels-at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. Database URL: https://miami-ad.org/.
Subject(s)
Aging , Alzheimer Disease , DNA Methylation , Humans , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , DNA Methylation/genetics , Aging/genetics , Male , Female , Databases, Genetic , Knowledge Bases , CpG Islands/geneticsABSTRACT
DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC v1.0 arrays. We conducted a comprehensive assessment of the EPIC v1.0 array probe reliability using 69 blood DNA samples, each measured twice, generated by the Alzheimer's Disease Neuroimaging Initiative study. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliability information for probes on the EPIC v1.0 array, will serve as a valuable resource for future DNAm studies.
Subject(s)
DNA Methylation , Quantitative Trait Loci , Oligonucleotide Array Sequence Analysis/methods , Reproducibility of Results , CpG IslandsABSTRACT
Rectal cancer (RC) presents significant treatment challenges, particularly in the context of chemotherapy resistance. Addressing this, our study pioneers the use of matched RC tumor tissue and patient-derived organoid (PDO) models coupled with the innovative computational tool, Moonlight, to explore the gene expression landscape of RC tumors and their response to chemotherapy. We analyzed 18 tissue samples and 32 matched PDOs, ensuring a high-fidelity representation of the tumor bioloy. Our comprehensive integration strategy involved differential expression analyses (DEAs) and gene regulatory network (GRN) analyses, facilitating the identification of 5,199 genes governing at least one regulon. By using the biological processes (BPs) collected from Moonlight closely related to cancer, we pinpointed 2,118 regulator-regulon groups with potential roles in oncogenic processes. Further, through integration of Moonlight and DEA results identified 334 regulator-regulon groups significantly enriched in both tissue and PDO samples, classifying them as oncogenic mediators (OMs). Among these, four genes (NCKAP1L, LAX1, RAD51AP1, and NAT2) demonstrated an association with drug responsiveness and recurrence-free survival (RFS), offering new insights into the molecular mechanisms of chemotherapy response in RC. Our integrated approach not only underscores the translational fidelity of PDOs, but also harnesses the analytical prowess of Moonlight, setting a new benchmark for targeted therapy research in rectal cancer.
ABSTRACT
Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.
Subject(s)
Diterpenes , Epoxy Compounds , Medulloblastoma , Phenanthrenes , Proto-Oncogene Proteins c-myc , Xenograft Model Antitumor Assays , Phenanthrenes/pharmacology , Diterpenes/pharmacology , Epoxy Compounds/pharmacology , Medulloblastoma/drug therapy , Medulloblastoma/genetics , Medulloblastoma/pathology , Medulloblastoma/metabolism , Animals , Humans , Mice , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Cell Line, Tumor , Prodrugs/pharmacology , Cerebellar Neoplasms/drug therapy , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , OrganophosphatesABSTRACT
Triple-negative breast cancer (TNBC) is a heterogeneous disease with varying responses to neoadjuvant chemotherapy (NAC). The identification of biomarkers to predict NAC response and inform personalized treatment strategies is essential. In this study, we conducted large-scale gene expression meta-analyses to identify genes associated with NAC response and survival outcomes. The results showed that immune, cell cycle/mitotic, and RNA splicing-related pathways were significantly associated with favorable clinical outcomes. Furthermore, we integrated and divided the gene association results from NAC response and survival outcomes into four quadrants, which provided more insights into potential NAC response mechanisms and biomarker discovery.
ABSTRACT
BACKGROUND: Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. METHODS: We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aß42, phosphorylated tau181 (pTau181), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. RESULTS: We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. CONCLUSIONS: Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/pathology , DNA Methylation , Brain/diagnostic imaging , Brain/pathology , Neuroimaging , Biomarkers/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluidABSTRACT
Background Growing evidence has demonstrated that DNA methylation (DNAm) plays an important role in Alzheimer's disease (AD) and that DNAm differences can be detected in the blood of AD subjects. Most studies have correlated blood DNAm with the clinical diagnosis of AD in living individuals. However, as the pathophysiological process of AD can begin many years before the onset of clinical symptoms, there is often disagreement between neuropathology in the brain and clinical phenotypes. Therefore, blood DNAm associated with AD neuropathology, rather than with clinical data, would provide more relevant information on AD pathogenesis. Methods We performed a comprehensive analysis to identify blood DNAm associated with cerebrospinal fluid (CSF) pathological biomarkers for AD. Our study included matched samples of whole blood DNA methylation, CSF Aß 42 , phosphorylated tau 181 (pTau 181 ), and total tau (tTau) biomarkers data, measured on the same subjects and at the same clinical visits from a total of 202 subjects (123 CN or cognitively normal, 79 AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. To validate our findings, we also examined the association between premortem blood DNAm and postmortem brain neuropathology measured on a group of 69 subjects in the London dataset. Results We identified a number of novel associations between blood DNAm and CSF biomarkers, demonstrating that changes in pathological processes in the CSF are reflected in the blood epigenome. Overall, the CSF biomarker-associated DNAm is relatively distinct in CN and AD subjects, highlighting the importance of analyzing omics data measured on cognitively normal subjects (which includes preclinical AD subjects) to identify diagnostic biomarkers, and considering disease stages in the development and testing of AD treatment strategies. Moreover, our analysis revealed biological processes associated with early brain impairment relevant to AD are marked by DNAm in the blood, and blood DNAm at several CpGs in the DMR on HOXA5 gene are associated with pTau 181 in the CSF, as well as tau-pathology and DNAm in the brain, nominating DNAm at this locus as a promising candidate AD biomarker. Conclusions Our study provides a valuable resource for future mechanistic and biomarker studies of DNAm in AD.
ABSTRACT
DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC arrays. We conducted a comprehensive assessment of the EPIC array probe reliability using 138 duplicated blood DNAm samples generated by the Alzheimer's Disease Neuroimaging Initiative study. We introduced a novel statistical measure, the modified intraclass correlation, to better account for the disagreement in duplicate measurements. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliable information for probes on the EPIC array, will serve as a valuable resource for future DNAm studies.
ABSTRACT
BACKGROUND: Sex is increasingly recognized as a significant factor contributing to the biological and clinical heterogeneity in AD. There is also growing evidence for the prominent role of DNA methylation (DNAm) in Alzheimer's disease (AD). METHODS: We studied sex-specific DNA methylation differences in the blood samples of AD subjects compared to cognitively normal subjects, by performing sex-specific meta-analyses of two large blood-based epigenome-wide association studies (ADNI and AIBL), which included DNA methylation data for a total of 1284 whole blood samples (632 females and 652 males). Within each dataset, we used two complementary analytical strategies, a sex-stratified analysis that examined methylation to AD associations in male and female samples separately, and a methylation-by-sex interaction analysis that compared the magnitude of these associations between different sexes. After adjusting for age, estimated immune cell type proportions, batch effects, and correcting for inflation, the inverse-variance fixed-effects meta-analysis model was used to identify the most consistent DNAm differences across datasets. In addition, we also evaluated the performance of the sex-specific methylation-based risk prediction models for AD diagnosis using an independent external dataset. RESULTS: In the sex-stratified analysis, we identified 2 CpGs, mapped to the PRRC2A and RPS8 genes, significantly associated with AD in females at a 5% false discovery rate, and an additional 25 significant CpGs (21 in females, 4 in males) at P-value < 1×10-5. In methylation-by-sex interaction analysis, we identified 5 significant CpGs at P-value < 10-5. Out-of-sample validations using the AddNeuroMed dataset showed in females, the best logistic prediction model included age, estimated immune cell-type proportions, and methylation risk scores (MRS) computed from 9 of the 23 CpGs identified in AD vs. CN analysis that are also available in AddNeuroMed dataset (AUC = 0.74, 95% CI: 0.65-0.83). In males, the best logistic prediction model included only age and MRS computed from 2 of the 5 CpGs identified in methylation-by-sex interaction analysis that are also available in the AddNeuroMed dataset (AUC = 0.70, 95% CI: 0.56-0.82). CONCLUSIONS: Overall, our results show that the DNA methylation differences in AD are largely distinct between males and females. Our best-performing sex-specific methylation-based prediction model in females performed better than that for males and additionally included estimated cell-type proportions. The significant discriminatory classification of AD samples with our methylation-based prediction models demonstrates that sex-specific DNA methylation could be a predictive biomarker for AD. As sex is a strong factor underlying phenotypic variability in AD, the results of our study are particularly relevant for a better understanding of the epigenetic architecture that underlie AD and for promoting precision medicine in AD.
Subject(s)
Alzheimer Disease , DNA Methylation , Alzheimer Disease/genetics , CpG Islands , Female , Humans , Male , Sex CharacteristicsABSTRACT
To better understand DNA methylation in Alzheimer's disease (AD) from both mechanistic and biomarker perspectives, we performed an epigenome-wide meta-analysis of blood DNA methylation in two large independent blood-based studies in AD, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that are significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four brain methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model includes age, sex, immune cell type proportions, and methylation risk score based on prioritized CpGs in cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P-value = 2.78 × 10-5). Our study offers new insights into epigenetics in AD and provides a valuable resource for future AD biomarker discovery.
Subject(s)
Alzheimer Disease , Epigenome , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Brain/pathology , DNA Methylation/genetics , Epigenesis, Genetic , Genome-Wide Association Study , HumansABSTRACT
BACKGROUND: Colorectal cancer is the second-leading cause of cancer-related mortality in the United States and a leading cause of cancer-related mortality worldwide. Loss of SMAD4, a critical tumor suppressor and the central node of the transforming growth factor-beta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNA-based profile associated with SMAD4 expression could be used to better identify high-risk colorectal cancer patients. AIM: Identify a gene expression-based SMAD4-modulated profile and test its association with patient outcome. METHODS AND RESULTS: Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMAD-binding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patient-derived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Disease-free survival was analyzed by the Kaplan-Meier method. In vitro analysis of three genes identified in the SMAD4-modulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with disease-free survival (p = .02, log-rank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with disease-free survival (p = .013, log-rank test). CONCLUSIONS: A SMAD4-modulated gene expression profile identified high-risk stage II and III colorectal cancer patients, can predict disease-free survival, and has prognostic potential for stage II and III colorectal cancer patients.
Subject(s)
Colorectal Neoplasms/genetics , Genetic Profile , Smad4 Protein/metabolism , Aged , Biomarkers, Tumor/genetics , Datasets as Topic , Disease-Free Survival , Female , Gene Expression , Humans , Male , Middle Aged , Progression-Free Survival , Risk AssessmentABSTRACT
Recent advances in technology have made multi-omics datasets increasingly available to researchers. To leverage the wealth of information in multi-omics data, a number of integrative analysis strategies have been proposed recently. However, effectively extracting biological insights from these large, complex datasets remains challenging. In particular, matched samples with multiple types of omics data measured on each sample are often required for multi-omics analysis tools, which can significantly reduce the sample size. Another challenge is that analysis techniques such as dimension reductions, which extract association signals in high dimensional datasets by estimating a few variables that explain most of the variations in the samples, are typically applied to whole-genome data, which can be computationally demanding. Here we present pathwayMultiomics, a pathway-based approach for integrative analysis of multi-omics data with categorical, continuous, or survival outcome variables. The input of pathwayMultiomics is pathway p-values for individual omics data types, which are then integrated using a novel statistic, the MiniMax statistic, to prioritize pathways dysregulated in multiple types of omics datasets. Importantly, pathwayMultiomics is computationally efficient and does not require matched samples in multi-omics data. We performed a comprehensive simulation study to show that pathwayMultiomics significantly outperformed currently available multi-omics tools with improved power and well-controlled false-positive rates. In addition, we also analyzed real multi-omics datasets to show that pathwayMultiomics was able to recover known biology by nominating biologically meaningful pathways in complex diseases such as Alzheimer's disease.
ABSTRACT
Cell-cell interactions (CCIs) and cell-cell communication (CCC) are critical for maintaining complex biological systems. The availability of single-cell RNA sequencing (scRNA-seq) data opens new avenues for deciphering CCIs and CCCs through identifying ligand-receptor (LR) gene interactions between cells. However, most methods were developed to examine the LR interactions of individual pairs of genes. Here, we propose a novel approach named LR hunting which first uses random forests (RFs)-based data imputation technique to link the data between different cell types. To guarantee the robustness of the data imputation procedure, we repeat the computation procedures multiple times to generate aggregated imputed minimal depth index (IMDI). Next, we identify significant LR interactions among all combinations of LR pairs simultaneously using unsupervised RFs. We demonstrated LR hunting can recover biological meaningful CCIs using a mouse cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) dataset and a triple-negative breast cancer scRNA-seq dataset.
ABSTRACT
Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology, and immune composition. TNBCs subtypes include two basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Through a comprehensive analysis of mutation, copy number, transcriptomic, epigenetic, proteomic, and phospho-proteomic patterns we describe the genomic landscape of TNBC subtypes. Mesenchymal subtype tumors display high mutation loads, genomic instability, absence of immune cells, low PD-L1 expression, decreased global DNA methylation, and transcriptional repression of antigen presentation genes. We demonstrate that major histocompatibility complex I (MHC-I) is transcriptionally suppressed by H3K27me3 modifications by the polycomb repressor complex 2 (PRC2). Pharmacological inhibition of PRC2 subunits EZH2 or EED restores MHC-I expression and enhances chemotherapy efficacy in murine tumor models, providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Subtype-specific differences in immune cell composition and differential genetic/pharmacological vulnerabilities suggest additional treatment strategies for TNBC.