Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.

Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation.

Genetic architecture of bone marrow fat fraction implies its involvement in osteoporosis risk.

Bone marrow adipose tissue, as a distinct adipose subtype, has been implicated in the pathophysiology of skeletal, metabolic, and hematopoietic disorders. To identify its underlying genetic factors, we utilized a deep learning algorithm capable of quantifying bone marrow fat fraction (BMFF) in the vertebrae and proximal femur using magnetic resonance imaging data of over 38,000 UK Biobank participants. Genome-wide association analyses uncovered 373 significant BMFF-associated variants (P-value < 5 × 10), with enrichment in bone remodeling, metabolism, and hematopoiesis pathway.

Genetic Control of tRNA-Derived Fragments Contributes to Cancer Risk.

Transfer RNA-derived fragments (tRFs) are a class of small non-coding RNAs that have exhibited several functions in cancer. Recent studies have shown that mutations in tRNA genes can lead to global changes in tRF expression levels and may affect tRF function, highlighting the need to further elucidate the regulation and functions of tRFs in cancer. Here, we conducted a pan-cancer analysis of tRF quantitative trait loci (tRFQTLs), encompassing 16,703 genetic variants associated with tRF expression across 31 cancer types.

Integrated Omics and Multi-Cohort Analyses Identify an Enhancer Variant Linking Ferroptosis to Precision Therapy in Prostate Cancer.

Prostate cancer is the most prevalent cancer among men worldwide and exhibits significant genetic heritability. In this study, we performed an integrative analysis combining chromatin accessibility profiling, transcriptomics, and two-stage case-control studies, alongside an unbiased phenome-wide exploration in the FinnGen cohort. This comprehensive approach identified the enhancer-associated single-nucleotide polymorphism rs7077830 at chromosome 10q11 as a critical modulator of prostate cancer susceptibility.

Identification and validation of blood leukocyte DNA methylation biomarkers for early detection of colorectal neoplasm.

Background: Identifying high-risk populations for colorectal cancer (CRC) is critical for precise screening. This study aimed to develop a novel risk prediction model using blood DNA methylation biomarkers to identify individuals at high risk for colorectal neoplasms.

Methods: The biomarker discovery phase involved 106 samples (56 advanced adenomas and 50 healthy controls) collected from the TARGET-C screening cohort between May 2018 and May 2021, which were analyzed using the Illumina Infinium MethylationEPIC v2.

Genetic Regulation of Alternative Polyadenylation Provides Novel Insights into Molecular Mechanisms Underlying Non-small Cell Lung Cancer.

Emerging evidence emphasizes the critical role of alternative polyadenylation (APA) in posttranscriptional regulation of genes, and APA-associated genetic variants (apaQTLs) show particular relevance for multiple disease. However, genetic regulation of APA and its role in non-small cell lung cancer (NSCLC) risk have not been thoroughly studied. Here, by leveraging genotype and APA data from The Cancer Genome Atlas, the association between genetic variation and APA is determined in NSCLC samples.

Single-cell eQTL Mapping Reveals Cell Subtype-specific Genetic Control and Mechanism in Malignant Transformation of Colorectal Cancer.

Unlabelled: Colorectal cancer is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. In this study, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular cross-talk during colorectal cancer development. Additionally, we created a colorectal cancer single-cell expression quantitative trait locus (sc-eQTL) map identifying 16,833 significant pairs across 28 cell subtypes, with more than 76% of sc-eQTLs being cell type-specific and fewer than 15% detectable in bulk datasets.

Environmental Chemical-Induced Cardiometabolic Disorders: Combined Epidemiological and Experimental Evidence.

Screening environmental pollutants that are harmful to the cardiometabolic status and understanding their key toxic pathways are crucial for effective clinical intervention. Based on exposure data of 46 chemicals in a nationally representative 13,286 people, logistic regression and mixture modeling were used to preliminarily identify environmental pollutants with significant impacts on 12 indicators for cardiometabolic disorders. A total of 15 chemicals were found to be associated with the integrated latent class, among which four chemicals (perfluorononanoic acid [PFNA], perfluorooctanoic acid [PFOA], thiocyanate, and thallium) also contributed significantly to the mixture effect.

Comprehensive analysis of transplacental transfer of environmental pollutants detected in paired maternal and cord serums.

Prenatal exposure to hazardous environmental pollutants is a critical global concern due to their confirmed presence in umbilical cord blood, indicating the ability of pollutants to cross the placental barrier and expose the fetus to harmful compounds. However, the transplacental transfer efficiencies (TTEs) of many pollutants remain underexplored. Herein, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively analyze 91 environmental pollutants, including 13 bisphenols (BPs), 18 organophosphorus flame retardants (OPFRs), 7 brominated and other flame retardants (BFRs), 34 phthalates (PAEs), and 19 per- and polyfluoroalkyl substances (PFASs), in paired maternal and cord serums.

Integrative functional screen of genomic loci uncovers CCND2 and its genetic regulatory mechanism in colorectal cancer development.

Although genome-wide association studies have identified dozens of loci associated with colorectal cancer (CRC) susceptibility, the causal genes or risk variants within these loci and their biological functions often remain elusive. Recently, the genomic locus 12p13.32, with the tag single-nucleotide polymorphism rs10774214, was identified as a crucial CRC risk locus in Asian populations.

A enhancer transcriptionally regulates Wnt signaling dosage to balance homeostasis and tumorigenesis of intestinal epithelia.

The β-catenin-dependent canonical Wnt signaling is pivotal in organ development, tissue homeostasis, and cancer. Here, we identified an upstream enhancer of - the coding gene for β-catenin, named ieCtnnb1 (ntestinal nhancer of ), which is crucial for intestinal homeostasis. ieCtnnb1 is predominantly active in the base of small intestinal crypts and throughout the epithelia of large intestine.

An atlas of genetic effects on cellular composition of the tumor microenvironment.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition.

Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development.

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations.

The global distribution and the risk prediction of relapsing fever group Borrelia: a data review with modelling analysis.

Background: The recent discovery of emerging relapsing fever group Borrelia (RFGB) species, such as Borrelia miyamotoi, poses a growing threat to public health. However, the global distribution and associated risk burden of these species remain uncertain. We aimed to map the diversity, distribution, and potential infection risk of RFGB.

Healthy dietary patterns, genetic risk, and gastrointestinal cancer incident risk: a large-scale prospective cohort study.

Background: Dietary patterns have been associated with several cancers, especially gastrointestinal cancer (GIC). However, whether a healthy dietary pattern could modify the risk of GIC among people with different genetic backgrounds is not clear.

Objective: The objective of the study was to investigate how dietary patterns and genetic susceptibility contribute to the risk of GIC independently and jointly.

Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks.

Genome-wide association studies (GWASs) have identified over 140 colorectal cancer (CRC)-associated loci; however, target genes at the majority of loci and underlying molecular mechanisms are poorly understood. Here, we utilized a Bayesian approach, integrative risk gene selector (iRIGS), to prioritize risk genes at CRC GWAS loci by integrating multi-omics data. As a result, a total of 105 high-confidence risk genes (HRGs) were identified, which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC.

A genetic variant in the immune-related gene ERAP1 affects colorectal cancer prognosis.

Background: Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism.

Methods: We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset.

Risk SNP in a transcript of RP11-638I2.4 increases lncRNA-YY1 interaction and pancreatic cancer susceptibility.

Tens of thousands of long non-coding RNAs (lncRNAs) have been identified through RNA-seq analysis, but the biological and pathological significance remains unclear. By integrating the genome-wide lncRNA data with a cross-ancestry meta-analysis of PDAC GWASs, we depicted a comprehensive atlas of pancreatic ductal adenocarcinoma (PDAC)-associated lncRNAs, containing 1,204 lncRNA (445 novel lncRNAs and 759 GENCODE annotated lncRNAs) and 4,368 variants. Furthermore, we found that PDAC-associated lncRNAs could function by altering chromatin activity, transcription factors, and RNA-binding proteins binding affinity.