Prospective of Mitochondrial DNA Variations in Cancer on Genomic Medicine.

Mitochondrial DNA (mtDNA) has emerged as a pivotal component in understanding the etiology and susceptibility of cancer. A recent study by Chen and colleagues delineated the germline genetic effect of mtDNA single-nucleotide polymorphisms (SNP) and haplogroups across pan-cancer risk. They identified a subset of mtSNPs and the corresponding risk score, as well as haplogroups A and M7 alongside their genetic interactions, conferring a protective effect against various cancers. These findings underscored the value of mtDNA variations as biomarkers for cancer etiology and as tools for cancer risk stratification. Future investigations are encouraged to integrate comprehensive omics data of genomics, transcriptomics, proteomics, and metabolomics, etc., from nuclear DNA with mtDNA variations, alongside single-cell and spatial technologies, to unravel the tumor mechanism and identify the drug targets. Moreover, the incorporation of polygenic risk score, that included mtDNA variations with both rare and common frequencies, and liquid biopsy-based biomarkers would enhance the predictive performance of cancer risk assessment and refine the risk stratification of population-based cancer screening. This commentary advocates for the validation across diverse populations to harness the full potential of mitochondrial genomics, and ultimately paves the prospective way for advancements in personalized cancer therapeutics and prevention strategies. See related article by Chen and colleagues, Cancer Epidemiol Biomarkers Prev 2024;33:381-8.

Genetic variants in C1GALT1 are associated with gastric cancer risk and immune infiltrations.

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-ß-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer susceptibility. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated these associations with a logistic regression model and identified that the rs35999583 in C1GALT1 was associated with gastric cancer risk (odd ratio, 0.83; 95% confidence interval [CI], 0.75-0.92; P = 3.95 × 10 -4]. C1GALT1 mRNA expression was significantly higher in gastric tumor tissues, and gastric cancer patients with higher C1GALT1 mRNA levels had the worse overall survival rates (hazards ratio, 1.33; 95% CI, 1.05-1.68; P log-rank = 1.90 × 10 -2). Furthermore, we found that C1GALT1 copy number variations differed in various immune cells and C1GALT1 mRNA expression was positively correlated with the infiltrating levels of CD4 + T cells and macrophages. These results highlight that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 to be a promising predictor of gastric cancer susceptibility and immune status.

Distinctive multicellular immunosuppressive hubs confer different intervention strategies for left- and right-sided colon cancers.

Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IShigh malignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Environmental pollutants exposure-derived extracellular vesicles: crucial players in respiratory disorders.

BACKGROUND: Individual exposure to environmental pollutants, as one of the most influential drivers of respiratory disorders, has received considerable attention due to its preventability and controllability. Considering that the extracellular vesicle (EV) was an emerging intercellular communication medium, recent studies have highlighted the crucial role of environmental pollutants derived EVs (EPE-EVs) in respiratory disorders. METHODS: PubMed and Web of Science were searched from January 2018 to December 2023 for publications with key words of environmental pollutants, respiratory disorders and EVs. RESULTS: Environmental pollutants could disrupt airway intercellular communication by indirectly stimulating airway barrier cells to secrete endogenous EVs, or directly transmitting exogenous EVs, mainly by biological pollutants. Mechanistically, EPE-EVs transferred specific contents to modulate biological functions of recipient cells, to induce respiratory inflammation and impair tissue and immune function, which consequently contributed to the development of respiratory diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, lung cancer and infectious lung diseases. Clinically, EVs could emerged as promising biomarkers and biological agents for respiratory diseases attributed by their specificity, convenience, sensibility and stability. CONCLUSIONS: Further studies of EPE-EVs are helpful to understand the aetiology and pathology of respiratory diseases, and facilitate the precision respiratory medicine in risk screening, early diagnosis, clinical management and biotherapy.

An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study.

BACKGROUND: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. METHODS: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. RESULTS: The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99-2.78] than LOPC (HR = 1.95, 95% CI 1.89-2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98-5.54) but not to LOPC (HR = 0.98, 95% CI 0.96-1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. CONCLUSIONS: This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment.

The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10-14; 543 patients) and 1.80 (P = 1.11 × 10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

Single-cell and multi-omics analyses highlight cancer-associated fibroblasts-induced immune evasion and epithelial mesenchymal transition for smoking bladder cancer.

Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens.

Combining fecal immunochemical testing and questionnaire-based risk assessment in selecting participants for colonoscopy screening in the Chinese National Colorectal Cancer Screening Programs: A population-based cohort study.

BACKGROUND: Screening reduces colorectal cancer (CRC) burden by allowing early resection of precancerous and cancerous lesions. An adequate selection of high-risk individuals and a high uptake rate for colonoscopy screening are critical to identifying people more likely to benefit from screening and allocating healthcare resources properly. We evaluated whether combining a questionnaire-based interview for risk factors with fecal immunochemical test (FIT) outcomes for high-risk assessment is more efficient and economical than a questionnaire-based interview-only strategy. METHODS AND FINDINGS: In this multicenter, population-based, prospective cohort study, we enrolled community residents aged 40 to 74 years in 29 provinces across China. From 2016 to 2020, a total of 1,526,824 eligible participants were consecutively enrolled in the Cancer Screening Program in Urban China (CanSPUC) cohort, and 940,605 were enrolled in the Whole Life Cycle of Cancer Screening Program (WHOLE) cohort, with follow-up to December 31, 2022. The mean ages were 56.89 and 58.61 years in CanSPUC and WHOLE, respectively. In the WHOLE cohort, high-risk individuals were identified by combining questionnaire-based interviews to collect data on risk factors (demographics, diet history, family history of CRC, etc.) with FIT outcomes (RF-FIT strategy), whereas in the CanSPUC cohort, high-risk individuals were identified using only interview-based data on risk factors (RF strategy). The primary outcomes were participation rate and yield (detection rate of advanced neoplasm, early-stage detection rate of CRCs [stage I/II], screening yield per 10,000 invitees), which were reported for the entire population and for different gender and age groups. The secondary outcome was the cost per case detected. In total, 71,967 (7.65%) and 281,985 (18.47%) individuals were identified as high-risk and were invited to undergo colonoscopy in the RF-FIT group and RF group, respectively. The colonoscopy participation rate in the RF-FIT group was 26.50% (19,071 of 71,967) and in the RF group was 19.54% (55,106 of 281,985; chi-squared test, p < 0.001). A total of 102 (0.53%) CRCs and 2,074 (10.88%) advanced adenomas were detected by the RF-FIT, versus 90 (0.16%) and 3,593 (6.52%) by the RF strategy (chi-squared test, both p < 0.001). The early-stage detection rate using the RF-FIT strategy was significantly higher than that by the RF strategy (67.05% versus 47.95%, Fisher's exact test, p = 0.016). The cost per CRC detected was $24,849 by the RF-FIT strategy versus $55,846 by the RF strategy. A limitation of the study was lack of balance between groups with regard to family history of CRC (3.5% versus 0.7%). CONCLUSIONS: Colonoscopy participation and screening yield were better with the RF-FIT strategy. The association with CRC incidence and mortality reduction should be evaluated after long-term follow-up.

Benzo[a]pyrene exposure affects colorectal cancer susceptibility by regulating ERß-mediated LINC02977 transcription.

Environmental pollutants known as polycyclic aromatic hydrocarbons (PAHs) are produced through the incomplete combustion of organic material. While PAHs have been investigated as genotoxicants, they can also operate through nongenotoxic pathways in estrogen-dependent malignancies, such as breast, cervical and ovarian cancer. However, whether PAHs induce colorectal cancer (CRC) risk through estrogenic effects is still illusive. Here, we systematically investigated the abnormal expression and activation of estrogen receptor beta (ERß) regulated by PAHs in CRC as well as the underlying mechanisms of ERß-mediated CRC risk. Based on the 300 plasma samples from CRC patients and healthy controls detected by GC-MS/MS, we found that the plasma concentrations of benzo[a]pyrene (BaP) were significantly higher in CRC cases than in healthy controls, with significant estrogenic effects. Moreover, histone deacetylase 2 (HDAC2)-induced deacetylation of the promoter decreases ERß expression, which is associated with poor overall survival and advanced tumor stage. The study also revealed that BaP and estradiol (E2) had different carcinogenic effects, with BaP promoting cell proliferation and inhibiting apoptosis, while E2 had the opposite effects. Additionally, this study mapped ERß genomic binding regions by performing ChIP-seq and ATAC-seq and identified genetic variants of rs1411680 and its high linkage disequilibrium SNP rs6477937, which were significantly associated with CRC risk through meta-analysis of two independent Chinese population genome-wide association studies comprising 2,248 cases and 3,173 controls and then validation in a large-scale European population. By integrating data from functional genomics, we validated the regulatory effect of rs6477937 as an ERß binding-disrupting SNP that mediated allele-specific expression of LINC02977 in a long-range chromosomal interaction manner, which was found to be highly expressed in CRC tissues. Overall, this study suggests that the different active effects on ERß by PAHs and endogenous E2 may play a crucial role in the development and progression of CRC and highlights the potential of targeting ERß and its downstream targets for CRC prevention and treatment.

Cigarette smoking combined with genetic variation regulates the m6A methylation of CRNKL1 and is associated with bladder cancer risk.

Cigarette smoking was known to accelerate the occurrence and development of bladder cancer by regulating RNA modification. However, the association between the combination of cigarette smoking and RNA modification-related single nucleotide polymorphisms (RNAm-SNPs) and bladder cancer risk remains unclear. In this study, 1681 participants, including 580 cases and 1101 controls, were recruited for genetic association analysis. In total, 1 287 990 RNAm-SNPs involving nine RNA modifications (m6A, m1A, m6Am, 2'-O-Me, m5C, m7G, A-to-I, m5U, and pseudouridine modification) were obtained from the RMVar database. The interactive effect of cigarette smoking and RNAm-SNPs on bladder cancer risk was assessed through joint analysis. The susceptibility analysis revealed that 89 RNAm-SNPs involving m6A, m1A, and A-to-I modifications were associated with bladder cancer risk. Among them, m6A-related rs2273058 in CRNKL1 was associated with bladder cancer risk (odds ratios (OR) = 1.35, padj = 1.78 × 10-4), and CRNKL1 expression was increased in bladder cancer patients (p = 0.035). Cigarette smoking combined with the A allele of rs2273058 increased bladder cancer risk compared with nonsmokers with the G allele of rs2273058 (OR = 2.40, padj = 3.11 × 10-9). Mechanistically, the A allele of rs2273058 endowed CRNKL1 with an additional m6A motif, facilitating recognition by m6A reader IGF2BP1, thereby promoting CRNKL1 expression under cigarette smoking (r = 0.142, p = 0.017). Moreover, elevated CRNKL1 expression may accelerate cell cycle and proliferation, thereby increasing bladder cancer risk. In summary, our study demonstrated that cigarette smoking combined with RNAm-SNPs contributes to bladder cancer risk, which provides a potential target for bladder cancer prevention.

Identification of genetic profile and biomarkers involved in acute respiratory distress syndrome.

PURPOSE: The purpose of this study was to profile genetic causal factors of acute respiratory distress syndrome (ARDS) and early predict patients at high ARDS risk. METHODS: We performed a phenome-wide Mendelian Randomization analysis through summary statistics of an ARDS genome-wide association study (1250 cases and 1583 controls of European ancestry) and 33,150 traits. Transcriptomic data from human blood and lung tissues of a preclinical mouse model were used to validate biomarkers, which were further used to construct a prediction model and nomogram. RESULTS: A total of 1736 traits, including 1223 blood RNA, 159 plasma proteins, and 354 non-gene phenotypes (classified by Biochemistry, Anthropometry, Disease, Nutrition and Habit, Immunology, and Treatment), exhibited a potentially causal relationship with ARDS development, which were accessible through a user-friendly interface platform called CARDS (Causal traits for Acute Respiratory Distress Syndrome). Regarding candidate blood RNA, four genes were validated, namely TMEM176B, SLC2A5, CDC45, and VSIG8, showing differential expression in blood of ARDS patients compared to controls, as well as dynamic expression in mouse lung tissues. Importantly, the addition of four blood genes and five immune cell proportions significantly improved the prediction performance of ARDS development, with 0.791 of the area under the curve from receiver-operator characteristic, compared to 0.725 for the basic model consisting of Acute Physiology and Chronic Health Evaluation (APACHE) III Score, sex, body mass index, bacteremia, and sepsis. A model-based nomogram was also developed for the clinical practice. CONCLUSION: This study identifies a wide range of ARDS relevant factors and develops a promising prediction model, enhancing early clinical management and intervention for ARDS development.

CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis. SIGNIFICANCE: The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.

PM2.5-derived exosomal long noncoding RNA PAET participates in childhood asthma by enhancing DNA damage via m6A-dependent OXPHOS regulation.

Fine particulate matter (PM2.5) is known to enhance DNA damage levels and is involved in respiratory diseases. Exosomes can carry noncoding RNAs, especially long noncoding RNAs (lncRNAs), as regulators of DNA damage, which participate in diseases. However, their role in PM2.5-induced childhood asthma remains unclear. We performed RNA-seq to profile aberrantly expressed exosomal lncRNAs derived from PM2.5-treated human bronchial epithelial (HBE) cell models. The role of exosomal lncRNAs in childhood asthma was determined in a case-control study. The intercellular communication mechanisms of exosomal lncRNA on DNA damage were determined in vitro. Exosomes secreted by PM2.5-treated HBE cells (PM2.5-Exos) could increase the DNA damage levels of recipient HBE cells and promote the expression levels of airway remodeling-related markers in sensitive human bronchial smooth muscle cells (HBSMCs). LncRNA PM2.5-associated exosomal transcript (PAET) was highly expressed in PM2.5-Exos and was associated with PM2.5 exposure in childhood asthma. Mechanistically, exosomal lncRNA PAET promoted methyltransferase-like 3 (METTL3) accumulation by increasing its stability, which stimulated N6-methyladenosine (m6A) modification of cytochrome c oxidase subunit 4I1 (COX4I1), and COX4I1 levels were decreased in a mechanism dependent on the m6A "reader" YTH domain family 3 (YTHDF3). COX4I1 deficiency subsequently disrupted oxidative phosphorylation (OXPHOS), resulting in attenuated adenosine triphosphate (ATP) production and accumulation of reactive oxygen species (ROS), which increased DNA damage levels. This comprehensive study extends the understanding of PM2.5-induced childhood asthma via DNA damage and identifies exosomal lncRNA PAET as a potential target for childhood asthma.

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk.

Aberrant alternative polyadenylation (APA) events play an important role in cancers, but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer. Previous genome-wide association study performed APA quantitative trait loci (apaQTL) analyses in bladder cancer, and identified 17 955 single nucleotide polymorphisms (SNPs). We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways, high mutational burden, and immune infiltration. Association analysis showed that apaQTL-associated SNPs rs34402449 C>A, rs2683524 C>T, and rs11540872 C>G were significantly associated with susceptibility to bladder cancer (rs34402449: OR = 1.355, 95% confidence interval [CI]: 1.159-1.583, P = 1.33 × 10 -4; rs2683524: OR = 1.378, 95% CI: 1.164-1.632, P = 2.03 × 10 -4; rs11540872: OR = 1.472, 95% CI: 1.193-1.815, P = 3.06 × 10 -4). Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer ( P trend = 2.87 × 10 -12). We found that PRR13, being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines, was more highly expressed in bladder cancer tissues than in adjacent normal tissues. Moreover, the rs2683524 T allele was correlated with shorter 3' untranslated regions of PRR13 and increased PRR13 expression levels. Collectively, our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

Association between Liver MRI Proton Density Fat Fraction and Liver Disease Risk.

Background A better understanding of the association between liver MRI proton density fat fraction (PDFF) and liver diseases might support the clinical implementation of MRI PDFF. Purpose To quantify the genetically predicted causal effect of liver MRI PDFF on liver disease risk. Materials and Methods This population-based prospective observational study used summary-level data mainly from the UK Biobank and FinnGen. Mendelian randomization analysis was conducted using the inverse variance-weighted method to explore the causal association between genetically predicted liver MRI PDFF and liver disease risk with Bonferroni correction. The individual-level data were downloaded between August and December 2020 from the UK Biobank. Logistic regression analysis was performed to validate the association between liver MRI PDFF polygenic risk score and liver disease risk. Mediation analyses were performed using multivariable mendelian randomization. Results Summary-level and individual-level data were obtained from 32 858 participants and 378 436 participants (mean age, 57 years ± 8 [SD]; 203 108 female participants), respectively. Genetically predicted high liver MRI PDFF was associated with increased risks of malignant liver neoplasm (odds ratio [OR], 4.5; P < .001), alcoholic liver disease (OR, 1.9; P < .001), fibrosis and cirrhosis of the liver (OR, 3.0; P < .004), fibrosis of the liver (OR, 3.6; P = .002), cirrhosis of the liver (OR, 3.8; P < .001), nonalcoholic steatohepatitis (OR, 7.7; P < .001), and nonalcoholic fatty liver disease (NAFLD) (OR, 4.4; P < .001). Individual-level evidence supported these associations after grouping participants based on liver MRI PDFF polygenic risk score (all P < .004). The mediation analysis indicated that genetically predicted high-density lipoprotein cholesterol, type 2 diabetes mellitus, and waist-to-hip ratio (mediation effects, 25.1%-46.3%) were related to the occurrence of fibrosis and cirrhosis of the liver, cirrhosis of the liver, and NAFLD at liver MRI PDFF (all P < .05). Conclusion This study provided evidence of the association between genetically predicted liver MRI PDFF and liver health. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Reeder and Starekova and Monsell in this issue.

LncRNA BCCE4 Genetically Enhances the PD-L1/PD-1 Interaction in Smoking-Related Bladder Cancer by Modulating miR-328-3p-USP18 Signaling.

Identification of cancer-associated variants, especially those in functional regions of long noncoding RNAs (lncRNAs), has become an essential task in tumor etiology. However, the genetic function of lncRNA variants involved in bladder cancer susceptibility remains poorly understood. Herein, it is identified that the rs62483508 G > A variant in microRNA response elements (MREs) of lncRNA Bladder cancer Cell Cytoplasm-Enriched abundant transcript 4 (BCCE4) is significantly associated with decreased bladder cancer risk (odds ratio = 0.84, P = 7.33 × 10-8 ) in the Chinese population (3603 cases and 4986 controls) but not in the European population. The protective genetic effect of the rs62483508 A allele is found in smokers or cigarette smoke-related carcinogen 4-aminobiphenyl (4-ABP) exposure. Subsequent biological experiments reveal that the A allele of rs62483508 disrupts the binding affinity of miR-328-3p to facilitate USP18 from miRNA-mediated degradation and thus specifically attenuates the downstream PD-L1/PD-1 interaction. LncRNA BCCE4 is also enriched in exosomes from bladder cancer plasma, tissues, and cells. This comprehensive study clarifies the genetic mechanism of lncRNA BCCE4 in bladder cancer susceptibility and its role in the regulation of the immune response in tumorigenesis. The findings provide a valuable predictor of bladder cancer risk that can facilitate diagnosis and prevention.

Construction, evaluation, and AOP framework-based application of the EpPRS as a genetic surrogate for assessing environmental pollutants.

BACKGROUND: Environmental pollutant measurement is essential for accurate health risk assessment. However, the detection of humans' internal exposure to pollutants is cost-intensive and consumes time and energy. Polygenic risk scores (PRSs) have been widely applied in genetic studies of complex trait diseases. It is important to construct a genetically relevant environmental surrogate for pollutant exposure and to explore its utility for disease prediction and risk assessment. OBJECTIVES: This study enrolled 714 individuals with complete genomic data and exposomic data on 22 plasma-persistent organic pollutants (POPs). METHODS: We first conducted 22 POP genome-wide association studies (GWAS) and constructed the corresponding environmental pollutant-based PRS (EpPRS) by clumping and P value thresholding (C + T), lassosum, and PRS-CS methods. The best-fit EpPRS was chosen by its regression R2. An adverse outcome pathway (AOP) framework was developed to assess the effects of contaminants on candidate diseases. Furthermore, Mendelian randomization (MR) analysis was performed to explore the causal association between POPs and cancer risk. RESULTS: The C + T method produced the best-performing EpPRSs for 7 PCBs and 4 PBDEs. EpPRSs replicated the correlations of environmental exposure measurements based on consistent patterns. The diagnostic performance of type 2 diabetes mellitus (T2DM) PRS was improved by the combined model of T2DM-EpPRS of PCB126/BDE153. Finally, the AKT1-mediated AOP framework illustrated that PCB126 and BDE153 may increase the risk of T2DM by decreasing AKT1 phosphorylation through the cGMP-PKG pathway and promoting abnormal glucose homeostasis. MR analysis showed that digestive system tumors, such as colorectal cancer and biliary tract cancer, are more sensitive to POP exposure. CONCLUSIONS: EpPRSs can serve as a proxy for assessing pollutant internal exposure. The application of the EpPRS to disease risk assessment can reveal the toxic pathway and mode of action linking exposure and disease in detail, providing a basis for the development of environmental pollutant control strategies.