Aortic dissection (AD) is a life-threatening cardiovascular emergency characterized by acute aortic wall injury and high mortality, yet effective pharmacological therapies remain limited. Macrophage infiltration and vascular smooth muscle cell (VSMC) phenotypic switching from contractile to synthetic states are central to AD pathogenesis, but the mechanisms mediating intercellular communication between macrophages and VSMCs are incompletely understood. Emerging evidence suggests that exosomes can transfer bioactive miRNAs between cells; however, whether M1 macrophage-derived exosomes promote AD progression through specific miRNA delivery and whether they can be engineered for therapeutic intervention have not been clearly defined. In this study, we demonstrate that M1 macrophage-derived exosomes deliver miR-155-5p to VSMCs, where it targets and suppresses SMAD5, activates the RHOA/ROCK pathway, and drives contractile-to-synthetic phenotypic switching, thereby accelerating AD progression. Through comprehensive physicochemical characterization, including TEM, NTA, Zeta potential, and stability assays, we show that M0 macrophage-derived exosomes can be successfully engineered to load Antago-miR-155-5p via electroporation with favorable encapsulation efficiency and colloidal stability. In a BAPN-induced mouse model of AD, intravenous administration of Antago-miR-155-5p-loaded M0-Exos significantly improved survival, reduced AD incidence and aortic dilation, and restored VSMC contractile markers. Biodistribution studies using DiR and CY5 labeling confirmed efficient accumulation of these engineered exosomes in the injured aorta, while macrophage depletion and rescue experiments validated the pathogenic role of M1-derived exosomes. These findings identify a novel M1 exosome–miR-155-5p–SMAD5/RHOA/ROCK signaling axis in AD and establish engineered M0 macrophage-derived exosomes as a promising bioactive material platform for targeted miRNA therapy in aortic dissection.

Genome-wide association studies (GWASs) have identified approximately 100 loci for lung cancer, but potential causal genes remain largely unknown. To address this, we conducted a lung tissue-specific transcriptome-wide association study (TWAS). Gene expression prediction models were constructed using data of adjacent normal lung tissues from our Vanderbilt Thoracic Biorepository (N=314) and normal lung tissues from the GTEx (N=466) and then applied to our lung cancer GWAS meta-analysis (55,174 cases and 1,294,174 controls). We identified 109 unique risk genes for lung cancer and its histological subtypes. Of them, 71 unique genes were novel discoveries, and 13 unique genes reside in novel loci. Smoking-conditional analysis revealed that 52 unique genes are unrelated to smoking behavior. Seven unique genes showed cell-type-specific colocalization within potential risk cell types, including the alveolar type I and II, dendritic, and natural killer cells. Seventeen unique genes are targeted of 58 drugs that have been approved or in Phase II or III trials. In addition, 22 unique potential causal genes were supported by both Mendelian randomization and colocalization. Functional validation identified three genes through in vitro knockdown experiments. Our study identified new lung cancer candidate risk genes and offered insights into lung cancer biology and future translational utilities.

Abstract Introduction: Aberrant DNA methylation is a hallmark of cancer. Identifying methylation sites (CpGs) associated with breast cancer risk may help to elucidate disease mechanisms and inform precision prevention. We conducted a multi-ancestry breast tissue-based methylome-wide association study (MeWAS) to discover breast cancer susceptibility CpGs. Methods: We profiled DNA methylation in normal breast tissue from 152 African ancestry and 267 European ancestry women using the Illumina MethylationEPIC array, with matched genotype data. We trained ancestry-specific genetic prediction models for each methylation marker, and then tested associations with breast cancer risk by applying S-PrediXcan to ancestry-matched breast cancer GWAS summary statistics (European:133,384 cases and 113,789 controls; African :18,044 cases and 22,187 controls)). We also performed stratified analyses by estrogen receptor status (ER+, ER−) and triple-negative breast cancer (TNBC). Then fixed effect inverse variance weighted meta-analysis was conducted using METAL. Methylation set enrichment analysis was evaluated using R missMethyl. Results: We successfully built 160,204 African ancestry and 166,069 European ancestry methylation imputation models (R > 0.1 and P < 0.05). Meta-analysis across ancestries identified 625 CpGs whose genetically predicted methylation levels were significantly associated with overall breast cancer risk (Bonferroni-adjusted P < 0.05), 458 (73.3%) of which have not been reported in prior breast tissue MeWAS. Notably, the significant association between genetically proxied methylation levels of cg23766285 and overall breast cancer risk were only observed among African Ancestry. Among 308 CpGs with valid prediction models in both ancestries, 265 (86.0%) showed concordant directions of association. We additionally identified 32, 11, and 11 CpGs that were exclusively associated with risk of ER+ and ER- breast cancer and TNBC at Bonferroni corrected P <0.05, respectively. CpGs associated with overall risk (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.02-1.39), ER- breast cancer (OR, 1.97; 95% CI, 1.29-3.05), and TNBC (OR, 2.12; 95% CI, 1.27-3.61) were enriched in promoter regions, whereas ER+-associated CpGs were not. The identified CpGs are involved in various biological processes, including hormone, p53, and KRAS signaling pathways. Discussion: This is the first multi-ancestry, large-scale, tissue-based MeWAS in breast cancer. Our findings offer novel insight into breast carcinogenesis and breast cancer disparities. Citation Format: Shuai Xu, Jiajun Shi, Y-Thanh Lu, Guochong Damon Jia, Fei Ye, Qiuyin Cai, Jirong Long. Multi-ancestry methylation-wide association analyses identifies putative risk methylation markers for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3608.

Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined. Using generalized linear mixed models, we analyze 218 TF ChIP-Seq datasets alongside GWAS data from 100,204 CRC cases and 154,587 controls of East Asian and European ancestries. We identify 51 TFs and TF-cofactor interactions, including VDR-cofactors, as key regulators of CRC risk. Integrating these TF insights with transcriptome-wide association studies (TWAS), we further evaluate associations between genetically predicted gene expression, alternative splicing, and alternative polyadenylation with CRC risk, using RNA-seq data from 364 Asian-ancestry and 707 European-ancestry individuals. Multi-ancestry TWAS identify 222 risk genes, including 95 novel genes and 48 potentially druggable targets. Single-cell analysis provides additional functional evidence supporting ~45% of these genes, and experimental validation confirms oncogenic roles for RHPN2, IRS2, and TXN. Our findings elucidate key TF-gene regulatory networks and uncover novel CRC risk genes.

BACKGROUND/OBJECTIVES:DNA methylation is a key epigenetic mechanism involved in gene regulation and chromatin stability and may be influenced by nutritional exposures. However, population-level evidence regarding associations between dietary vitamin intake and genome-wide DNA methylation remains limited. METHODS:We investigated associations between dietary intake of vitamins A, B1, B2, B3, B6, B12, and E and blood DNA methylation in 2030 participants from the Southern Community Cohort Study (SCCS). Dietary intake was assessed using a validated Food Frequency Questionnaire, and genome-wide DNA methylation was profiled using the Illumina Infinium MethylationEPIC v2.0 BeadChip. Epigenome-wide association analyses were conducted using robust linear regression models adjusted for demographic, lifestyle, and estimated cellular composition variables. RESULTS:We identified 34 CpG sites associated with dietary intake of vitamins B1, B2, B3, B6, and E, at a false discovery rate-adjusted p-value (FDR_p) threshold of <0.1. The strongest association was observed between vitamin B6 intake and cg19831775 (Beta = -0.111, FDR_p = 0.015). No statistically significant associations were identified for vitamins A and B12. Most observed effects were modest, and associations were locus-specific rather than global. Race- and sex-stratified analyses demonstrated generally consistent directions of association, although statistical significance was attenuated in subgroup analyses. CONCLUSIONS:These findings provide suggestive evidence that dietary intake of vitamins B1, B2, B3, B6 and E may be associated with subtle variation in DNA methylation at specific genomic loci.

Background:Proteins directly impact disease development and act as drug targets. Therefore, we integrated genomic and lung tissue proteomics data to identify lung cancer susceptibility proteins, elucidating genetic mechanisms and candidate drug targets. Method:We profiled the proteome and genome in non-neoplastic lung tissue from 200 lung cancer patients. Using this data, we constructed genetic models to predict abundance across the proteome in lung tissue. We applied these models to genome-wide association study (GWAS) data from 55,174 lung cancer cases and 1,294,174 controls to evaluate their associations with the risk of lung cancer, overall and by major histological subtypes. Bayesian colocalization and Mendelian randomization (MR) analyses were used to prioritize putative causal proteins, which were cross-referenced with three main drug-protein databases to identify potential therapeutic targets. Results:We identified 29 proteins associated with lung cancer risk at a false discovery rate < 5%, including 25 for overall lung cancer, two (AQP3 and IL18) specifically for adenocarcinoma, and another two (HMGN2 and HLA-DMB) for squamous cell carcinoma. Of them, genes encoding 17 proteins reside at least 2Mb away from any known GWAS risk loci, including 14 for overall lung cancer (HYI, GPX1, GMPPB, DSP, HDDC2, MTCH2, SUOX, JMJD7, PDIA3, IL16, IQGAP1, SULT1A2, ARHGAP27, and TYMP) and three for subtypes (AQP3, IL18, and HMGN2). Among the 12 proteins located within the known risk loci, EPHX2, CLDN18, PSMD5, and CYP2S1 proteins showed an association independent of the proximal GWAS-identified lead variant. Colocalization and/or MR analysis suggested 11 potential causal proteins. Five of these candidate causal proteins (DSP, CLDN18, IQGAP1, IL18 and TYMP) are targeted by nine drugs already approved by the FDA or in phase III trials. Conclusion:Our study identified novel lung cancer susceptibility proteins and potential drug targets, offering valuable insights into lung cancer biology and future translational utilities.

Introduction Cigarette smoking and alcohol drinking are well-known risk factors for various cancers. We aimed to determine a comprehensive profile of cancer risk associated with these lifestyle factors in predominantly low-income Americans. Methods We prospectively investigated the associations between cigarette smoking, alcohol drinking, and the risk of twelve cancer types among over 74 000 low-income Black and White adults from the Southern Community Cohort Study in the United States. We used the Cox proportional hazards models to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for these associations. Results Compared to never smokers, current smokers had an increased HR for cancers of lung (HR: 14.14, 95% CI: 11.47-17.42), liver and bile duct (HR: 3.19, 95% CI: 2.40-4.25), kidney (HR: 1.47, 95% CI: 1.10-1.96), pancreas (HR: 1.88, 95% CI: 1.41-2.50), oral and pharynx (HR: 3.83, 95% CI: 2.70-5.42), and bladder (HR: 2.81, 95% CI: 1.92-4.11), and a reduced risk of prostate cancer (HR: 0.78, 95% CI: 0.68-0.89) and uterine cancer (HR: 0.45, 95% CI: 0.32-0.63); former smokers also exhibited elevated risks for cancers of lung, liver and bile duct, kidney, and bladder; however, a decreased risk for the lung, liver and bile duct, and bladder cancers was observed with longer durations of smoking cessation, with HRs from 9.71, 2.26, and 2.28 for a duration of <10 years down to 4.28, 1.58, and 1.42 for a duration of 10-19 years, respectively. Compared to never-drinkers, participants who consumed more than 2 drinks per day had increased risks of liver and bile duct cancer (HR: 1.66, 95% CI: 1.29-2.13) and oral and pharynx cancer (HR: 2.15, 95% CI: 1.58-2.91). Conclusion Cigarette smoking and alcohol drinking were associated with an increased risk of multiple cancers. Our findings support efforts to control cigarette and alcohol consumption for cancer prevention in low-income U.S. populations.

The role of Hippo-Yes-associated protein (YAP) in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r = 0.53, P < .0001) and nuclear β-catenin (r = 0.26, P = .0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P = .05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR = 12.62, 95% CI = 4.57-34.86, P trend < .001), which persisted after adjusting for covariates and biomarkers (OR = 12.31, 95% CI = 3.78-40.10, P trend < .0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced versus nonadvanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR = 16.82, 95% CI = 4.41-64.08, P < .0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.

Previous studies have linked liver diseases to lung cancer (LC) risk; however, few studies evaluated the associations of circulating liver enzyme levels with LC risk. We conducted a study of 353 incident LC cases and 646 matched controls with baseline serum alanine aminotransferase (ALT) and of 548 cases and 1032 matched controls with baseline serum alkaline phosphatase (ALP) nested within the Southern Community Cohort Study. Conditional logistic regression and generalized linear models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among all study participants and by stratification of potential effect modifiers. Most participants had clinically normal liver enzyme levels. Higher serum ALT levels were associated with reduced LC risk. Compared with the lowest tertile, participants in the second and third tertiles had OR (95% CI) of 0.74 (0.48-1.14) and 0.47 (0.28-0.78) (P-trend < .01), respectively. The inverse association was observed in African Americans (AAs) and European Americans, which was especially prominent among men, and was seen in both those diagnosed within [ORT3 (versus) (T1) = 0.41 (0.19-0.88)] and beyond [ORT3 (versus) (T1) = 0.35 (0.17-0.73)] a median follow-up time of 39 months. Higher serum ALP levels were associated with increased LC risk among AA men only [ORT3 (versus) (T1) = 2.01 (1.19-3.39)] (P-trend < .01). Our results indicate that in a predominantly low-income American population, higher serum ALT levels may be related to lower LC risk. Further studies are warranted to confirm our findings and elucidate the potential underlying biological mechanisms of the associations.

Physical activity (PA) has been suggested to influence the gut microbiome. We evaluated this association among low-income Black American adults. This study included 489 self-identified Black American participants from the Southern Community Cohort Study. PA data, including exercise/sport- and work/home-related moderate-vigorous PA (MVPA), was collected at cohort enrollment (2002−2009). Stool samples were collected between 2018 and 2021, and microbial composition was profiled using shotgun metagenomic sequencing. General linear regression models were employed to evaluate associations between PA and gut microbial α-diversity, abundance of individual species and metabolic pathways. Among all participants, MVPA measures were not associated with Shannon α-diversity (p > 0.05) and explained approximately 0.2−0.3% variation of Bray–Curtis dissimilarity. A total of 32 bacterial species, including seven Bacteroides species, two Streptococcus species, two Prevotella species, and nine microbial metabolic pathways, including D-fucofuranose biosynthesis, xyloglucan degradation, biosynthesis of L-citrulline, L-aspartate and L-asparagine biosynthesis, and urea cycle, were significantly associated with work/home-related and/or total MVPA (all false discovery rates < 0.10). In conclusion, MVPA, particularly from work and home activities, may modulate the composition and functionality of the gut microbiome among Black American adults.

BACKGROUND:Genome-wide association studies (GWAS) have identified over 80 susceptibility loci for lung cancer risk. However, the genes underlying these associations remain largely unknown. METHODS:We conducted a large transcriptome-wide association study (TWAS) to identify lung cancer susceptibility genes. We leveraged gene expression data from lungs and 48 other tissue types and whole-genome sequencing data from up to 706 samples of European ancestry in the GTEx (version 8) to build lung-tissue and joint-tissue gene expression prediction models. These models were applied to GWAS data, including 29,266 lung cancer cases and 56,450 controls, to assess the associations of genetically predicted gene expression levels with lung cancer risk. RESULTS:A total of 8624 genes were successfully built for single-tissue models, and 11,341 genes for joint-tissue models (12,133 unique genes altogether). Among 40 genes whose expression levels were associated with the risk of lung cancer at a Bonferroni-corrected significance level, ZKSCAN4 was located more than 2 Mb away from the GWAS-identified variants linked to lung cancer. Among the remaining 39 genes within 2 Mb of GWAS-identified variants, seven genes were independent of these. Among 53 genes associated with the risk of lung cancer subtypes, 13 genes were beyond 2 Mb of GWAS-identified variants, and four genes were independent of the GWAS-identified variants within 2 Mb regions. CONCLUSION:Our TWAS identified over 50 candidate susceptibility genes for lung cancer, providing new insights into lung cancer genetics.

Background: Patients with certain psychiatric disorders have increased lung cancer incidence. However, establishing a causal relationship through traditional epidemiological methods poses challenges. Methods: Available summary statistics of genome-wide association studies of cigarette smoking, lung cancer, and eight psychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), autism, depression, major depressive disorder, bipolar disorder, insomnia, neuroticism, and schizophrenia (range N: 46,350-1,331,010) were leveraged to estimate genetic correlations using Linkage Disequilibrium Score Regression and assess causal effect of each psychiatric disorder on lung cancer using two -sample Mendelian randomization (MR) models, comprising inverse -variance weighted (IVW), weighted median, MR -Egger, pleiotropy residual sum and outlier testing (MR-PRESSO), and a constrained maximum likelihood approach (cML-MR). Results: Significant positive correlations were observed between each psychiatric disorder and both smoking and lung cancer (all FDR < 0.05), except for the correlation between autism and lung cancer. Both univariable and the cML-MA MR analyses demonstrated that liability to schizophrenia, depression, ADHD, or insomnia was associated with an increased risk of overall lung cancer. Genetic liability to insomnia was linked specifically to squamous cell carcinoma (SCC), while genetic liability to ADHD was associated with an elevated risk of both SCC and small cell lung cancer (all P < 0.05). The later was further supported by multivariable MR analyses, which accounted for smoking. Limitations: Participants were constrained to European ancestry populations. Causal estimates from binary psychiatric disorders may be biased. Conclusion: Our findings suggest appropriate management of several psychiatric disorders, particularly ADHD, may potentially reduce the risk of developing lung cancer.

BACKGROUND:Alcohol intake can alter gut microbiome, which may subsequently affect human health. However, limited population-based, prospective studies have investigated associations of habitual and recent alcohol intake with the gut microbiome, particularly among Black/African American individuals. OBJECTIVE:We examined the association of alcohol intake with gut microbiome in a predominantly low-income Black/African American population. METHODS:We investigated the dose- and type-specific associations of habitual and recent alcohol intake with the gut microbiome among 538 Black/African American adults (150 males and 388 females). Habitual and recent alcohol intakes were assessed at cohort baseline (2002-2009) and stool collection (2018-2021), respectively. Gut microbiome was profiled using shotgun metagenomic sequencing. Generalized linear models were employed to evaluate the associations between alcohol intakes and gut microbiome composition, with adjustments for sociodemographic characteristics, other lifestyle factors, and comorbidities. False discovery rate (FDR) <0.1 was considered statistically significant. RESULTS:The mean age at enrollment was 53.2 ± 7.7 y, with a mean interval of 13.8 y (range: 9.0-18.1 y) between baseline and stool sample collection. Recent alcohol intake was not significantly associated with microbial taxa abundance. However, habitual alcohol intake, both total amount and types of alcoholic beverages, showed significant associations with several microbial taxa abundance, primarily in males, including species within classes Clostridia, Bacilli, and Mahellia within Firmicutes. Specifically, total alcohol, beer, and red wine intakes were all inversely associated with genus MGYG-HGUT-02719 within class Clostridia (β = -2.26 to -0.09 per 1 drink/d increase). Red wine consumption was also inversely associated with the abundance of genera CAG-110, Oscillibacter, and Gemmiger within class Clostridia (β = -3.88 to -2.69), whereas positively associated with genus Absiella (β = 1.81) within class Bacilli. Most of these associations remained significant after additionally adjusting for BMI and baseline comorbidities. CONCLUSIONS:We identified gut microbial taxa associated with habitual alcohol intake among Black/African American males, although the magnitudes of these associations were generally small. Further research is needed to determine if these bacteria modify alcohol-disease relationships.

We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC). Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses. Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95

Abstract About 70-80% of sporadic colorectal cancers (CRCs) harbor APC mutations. Whether specific characteristics of APC mutation or APC-related signaling pathways contribute to tumor initiation, advanced progression, and recurrence in the precancerous lesions remain to be elucidated. This study included145 sporadic precancerous adenomas from the Tennessee Colorectal Polyp Study. Expression of six APC-related proteins (β-catenin, p-YAP, CtBP, EB1, Asef, and N-terminal APC) in adenoma and non-tumor tissues (n=22) were quantitatively detected by immunohistochemistry. Targeted sequencing of APC was done for 108 adenomas. Metachronous adenoma status was obtained from chart review. YAP-correlated genes and their functional enrichment analysis were conducted using gene expression data of 326 adenomas from the Gene Expression Omnibus database. We found that nuclear β-catenin and p-YAP overexpression only existed in adenoma tissue, correlated with each other (r=0.26, P=0.0018), and associated with APC mutations (P=0.05). P-YAP was strongly associated with odds of large adenomas (OR=14.25, 95%CI=3.32-61.18, P trend<0.0001), villous growth pattern (OR=58.71, 95%CI=10.49-328.61, P trend<0.0001) and advanced adenomas (OR=12.62, 95%CI 4.57-34.86, P trend<0.001), and showed a significant interaction with nuclear β-catenin on advanced tumor (OR=16.82, 95%CI 4.41-64.08, P<0.0001). After adjusting for selected covariates and mutually adjusting for biomarkers with P<0.20 in crude models, p-YAP overexpression remained significantly associated with advanced adenomas (OR=12.31, 95% CI=3.78-40.10, P trend<0.0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways with predominantly pro-tumorigenic alterations. APC mutation and selected biomarkers were not significantly associated with metachronous adenoma. In conclusion, p-YAP overexpression might be a promising biomarker for high-risk sporadic adenoma. In addition to its synergistic effect with nuclear β-catenin, p-YAP may play tumorigenic roles through interaction with other cancer pathways in human sporadic adenoma. This study provided new evidence for oncogenic effects of p-YAP in human sporadic adenomas and shed light on the complex network of Hippo, Wnt, and other oncogenic signaling pathways. Citation Format: Lei Fan, Xingyi Guo, Mary Kay Washington, Jiajun Shi, Reid M. Ness, Qi Liu, Wanqing Wen, Xiao Liu, Qiuyin Cai, Wei Zheng, Robert J. Coffey, Martha J. Shrubsole, Timothy Su. Phospho-YAP (Ser127) overexpression is associated with sporadic advanced adenomas: The Tennessee Colorectal Polyp Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4769.

Abstract Introduction Genome-wide association studies (GWAS) have identified >60 genomic loci for lung cancer risk. However, causal genes and the underlying biological mechanisms for most of these loci remain unknown. Therefore, we conducted a multi-omics study to identify lung cancer susceptibility genes. Method We first conducted a transcriptome-wide association study (TWAS) using S-PrediXcan framework. Whole transcriptome data from adjacent-normal lung tissue samples and genomic data from 304 European-ancestry lung cancer patients were used to build genetic prediction models for expression levels of protein-coding genes and lincRNAs. The prediction models were then applied to GWAS meta-analysis results for lung cancer with 39,363 cases and 621,480 controls of European descents from TRICL-ILCCO, the UK Biobank, and FinnGen. COJO was used to assess whether those significant genes were independent of proximal (±1.5 Mb) GWAS-identified risk variants. To replicate our TWAS-identified genes, we used data from GTEx version 8 normal lung tissue (N=444) to build imputation models and then run association analyses. We acquired gene (N=107) and protein expression data (N=111) from tumor and matched adjacent-normal lung tissues from European-ancestry participants in the Clinical Proteomic Tumor Analysis Consortium. Paired Wilcoxon rank sum tests were then conducted to assess whether identified genes and their corresponding proteins were expressed differentially. Results Out of 18,850 genes (read count >6 and TPM >0.1 in at least 20% samples), 6,754 protein-coding genes and 802 lincRNAs were predicted reliably using genetic variants (R>0.1 and P<0.05). Among them, genetically proxied expression levels of 24 genes located at 15 loci were significantly associated with lung cancer risk at a Bonferroni adjusted P <0.05. Four genes were located at four novel loci, including SERF1A at 5q13.2, SMIM33 at 5q31.2, MUC5B at 11p15.5, and RASSF10 at 11p15.2. Six putative candidate genes, namely H4C13, HCP5B, STN1, COPS2, SKIV2L, and LINC00243 resided in previously GWAS-identified lung cancer loci but have not been reported. Of these six genes, SKIV2L (Padjust=1.49e-5) and LINC00243 (Padjust=3.47e-5) were independently associated with lung cancer risk even after adjusting for GWAS-identified variants. Among 24 identified genes, 16 showed a consistent significant association with lung cancer risk (p<0.05) based on the prediction models built using GTEx data. Of ten unreported or novel genes, MUC5B, SMIM33, SERF1A, STN1, COPS2, and LINC00243 showed differential gene expression at P <0.05 and consistent association direction with TWAS results. Three proteins, STN1, COPS2, and SKIV2L, showed differential expression in tumor and adjacent-normal tissue at P<0.05, which is consistent with our TWAS direction. Conclusion Our findings offer novel insights into lung cancer carcinogenesis by uncovering new genes and loci. Citation Format: Shuai Xu, Yaohua Yang, Tianying Zhao, Jiajun Shi, Jie Ping, Wanqing Wen, Hui Cai, Xingyi Guo, Ran Tao, Xiao-Ou Shu, Wei Zheng, Jirong Long, Qiuyin Cai. Multi Omics analyses identified novel loci and genes for lung cancer risk among European Descendants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB146.

Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

Background: Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates.Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation.Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation.However, the mechanism(s) underlying this association remains elusive.Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation.Methods: Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database.Three-week-old male S100A4 overexpression (AAV9-S100A4 OE) and S100A4 knockdown (AAV9-S100A4 KD) mice were exposed to β-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model.Results: S100A4 was observed to be the hub gene in aortic dissection.Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression.In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs.Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD.S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development.Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX.Conclusions: Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD.These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD.