DA-TransUNet: integrating spatial and channel dual attention with transformer U-net for medical image segmentation.

Accurate medical image segmentation is critical for disease quantification and treatment evaluation. While traditional U-Net architectures and their transformer-integrated variants excel in automated segmentation tasks. Existing models also struggle with parameter efficiency and computational complexity, often due to the extensive use of Transformers. However, they lack the ability to harness the image's intrinsic position and channel features. Research employing Dual Attention mechanisms of position and channel have not been specifically optimized for the high-detail demands of medical images. To address these issues, this study proposes a novel deep medical image segmentation framework, called DA-TransUNet, aiming to integrate the Transformer and dual attention block (DA-Block) into the traditional U-shaped architecture. Also, DA-TransUNet tailored for the high-detail requirements of medical images, optimizes the intermittent channels of Dual Attention (DA) and employs DA in each skip-connection to effectively filter out irrelevant information. This integration significantly enhances the model's capability to extract features, thereby improving the performance of medical image segmentation. DA-TransUNet is validated in medical image segmentation tasks, consistently outperforming state-of-the-art techniques across 5 datasets. In summary, DA-TransUNet has made significant strides in medical image segmentation, offering new insights into existing techniques. It strengthens model performance from the perspective of image features, thereby advancing the development of high-precision automated medical image diagnosis. The codes and parameters of our model will be publicly available at https://github.com/SUN-1024/DA-TransUnet.

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.

Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing.

The current study aimed to investigate associations of circRNAs and related genetic variants with risk of prostate cancer (PCa) as well as to elucidate biological mechanisms underlying the associations. By using the MiOncoCirc database, we first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify risk-associated circRNAs. We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls, and identified circHIBADH rs11973492 as a significant risk-associated variant (odds ratio = 1.20, 95% confidence interval: 1.08-1.34, P = 7.06 × 10 -4) in a dominant genetic model, which altered the secondary structure of the corresponding RNA chain. In the in silico analysis, we found circHIBADH to sponge and silence 21 RNA-binding proteins (RPBs) enriched in the RNA splicing pathway, among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house (four tissue samples) and publicly available single-cell transcriptomes. Additionally, we demonstrated that HNRNPA1 might influence hallmarks including MYC, DNA repair, and E2F target signaling pathways, thereby promoting carcinogenesis. In conclusion, genetic variants in circHIBADH may act as a sponge and inhibitor of RNA splicing-associated RBPs including HNRNPA1, playing an oncogenic role in PCa.

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.

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.

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.

Mining User Reviews From Hypertension Management Mobile Health Apps to Explore Factors Influencing User Satisfaction and Their Asymmetry: Comparative Study.

BACKGROUND: Hypertension significantly impacts the well-being and health of individuals globally. Hypertension management apps (HMAs) have been shown to assist patients in controlling blood pressure (BP), with their efficacy validated in clinical trials. However, the utilization of HMAs continues to be suboptimal. Presently, there is a dearth of real-world research based on big data and exploratory mining that compares Chinese and American HMAs. OBJECTIVE: This study aims to systematically gather HMAs and their user reviews from both China and the United States. Subsequently, using data mining techniques, the study aims to compare the user experience, satisfaction levels, influencing factors, and asymmetry between Chinese and American users of HMAs. In addition, the study seeks to assess the disparities in satisfaction and its determinants while delving into the asymmetry of these factors. METHODS: The study sourced HMAs and user reviews from 10 prominent Chinese and American app stores globally. Using the latent Dirichlet allocation (LDA) topic model, the research identified various topics within user reviews. Subsequently, the Tobit model was used to investigate the impact and distinctions of each topic on user satisfaction. The Wald test was applied to analyze differences in effects across various factors. RESULTS: We examined a total of 261 HMAs along with their associated user reviews, amounting to 116,686 reviews in total. In terms of quantity and overall satisfaction levels, Chinese HMAs (n=91) and corresponding reviews (n=16,561) were notably fewer compared with their American counterparts (n=220 HMAs and n=100,125 reviews). The overall satisfaction rate among HMA users was 75.22% (87,773/116,686), with Chinese HMAs demonstrating a higher satisfaction rate (13,866/16,561, 83.73%) compared with that for American HMAs (73,907/100,125, 73.81%). Chinese users primarily focus on reliability (2165/16,561, 13.07%) and measurement accuracy (2091/16,561, 12.63%) when considering HMAs, whereas American users prioritize BP tracking (17,285/100,125, 17.26%) and data synchronization (12,837/100,125, 12.82%). Seven factors (easy to use: P<.001; measurement accuracy: P<.001; compatibility: P<.001; cost: P<.001; heart rate detection function: P=.02; blood pressure tracking function: P<.001; and interface design: P=.01) significantly influenced the positive deviation (PD) of Chinese HMA user satisfaction, while 8 factors (easy to use: P<.001; reliability: P<.001; measurement accuracy: P<.001; compatibility: P<.001; cost: P<.001; interface design: P<.001; real-time: P<.001; and data privacy: P=.001) affected the negative deviation (ND). Notably, BP tracking had the greatest effect on PD (ß=.354, P<.001), while cost had the most significant impact on ND (ß=3.703, P<.001). All 12 factors (easy to use: P<.001; blood pressure tracking function: P<.001; data synchronization: P<.001; blood pressure management effect: P<.001; heart rate detection function: P<.001; data sharing: P<.001; reliability: P<.001; compatibility: P<.001; interface design: P<.001; advertisement distribution: P<.001; measurement accuracy: P<.001; and cost: P<.001) significantly influenced the PD and ND of American HMA user satisfaction. Notably, BP tracking had the greatest effect on PD (ß=0.312, P<.001), while data synchronization had the most significant impact on ND (ß=2.662, P<.001). In addition, the influencing factors of PD and ND in user satisfaction of HMA in China and the United States are different. CONCLUSIONS: User satisfaction factors varied significantly between different countries, showing considerable asymmetry. For Chinese HMA users, ease of use and interface design emerged as motivational factors, while factors such as cost, measurement accuracy, and compatibility primarily contributed to user dissatisfaction. For American HMA users, motivational factors were ease of use, BP tracking, BP management effect, interface design, measurement accuracy, and cost. Moreover, users expect features such as data sharing, synchronization, software reliability, compatibility, heart rate detection, and nonintrusive advertisement distribution. Tailored experience plans should be devised for different user groups in various countries to address these diverse preferences and requirements.

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.

A Multiethnic Germline-Somatic Association Database Deciphers Multilayered and Interconnected Genetic Mutations in Cancer.

Inherited germline and acquired somatic alterations can both promote human tumor development. Elucidating the cooperation between somatic and germline genetic alterations that drive tumorigenesis could help inform precision cancer prevention and treatment strategies. Here, leveraging genomic genotyping and sequencing data from 9,029 patients with cancer with European, East Asian, and African ancestry, we performed a pan-cancer analysis to evaluate the associations between germline SNPs and somatic alterations, including single-nucleotide variant and small insertion/deletion mutations, copy-number variation, tumor mutational burden, and mutational signatures. Genome-wide significant germline-somatic pairs were abundant, and most of the associations were observed in one cancer type and one ancestry group. A user-friendly interactive Multiethnic Germline-Somatic Association (MGSA) database (http://wanglab-hkust.cn:3838/MGSA/) was developed, which can be used to query, browse, and download the results of the association analyses. Moreover, the MGSA database offers additional survival analysis and functional annotation. Together, this work provides a resource for uncovering the clinical and biological roles of associations between germline variants and somatic alterations in human cancer. SIGNIFICANCE: Comprehensive analysis of connections between germline variants and somatic events in cancer offers a resource for investigating the functional significance of genetic mutations and exploring genetic factors contributing to racial disparities.

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.

A new early warning method for mild cognitive impairment due to Alzheimer's disease based on dynamic evaluation of the "spatial executive process".

Objective: Mild cognitive impairment (MCI) due to Alzheimer's disease (AD), as an early stage of AD, is an important point for early warning of AD. Neuropathological studies have shown that AD pathology in pre-dementia patients involves the hippocampus and caudate nucleus, which are responsible for controlling cognitive mechanisms such as the spatial executive process (SEP). The aim of this study is to design a new method for early warning of MCI due to AD by dynamically evaluating SEP. Methods: We designed fingertip interaction handwriting digital evaluation paradigms and analyzed the dynamic trajectory of fingertip interaction and image data during "clock drawing" and "repetitive writing" tasks. Extracted fingertip interaction digital biomarkers were used to assess participants' SEP disorders, ultimately enabling intelligent diagnosis of MCI due to AD. A cross-sectional study demonstrated the predictive performance of this new method. Results: We enrolled 30 normal cognitive (NC) elderly and 30 MCI due to AD patients, and clinical research results showed that there may be neurobehavioral differences between the two groups in digital biomarkers captured during SEP. The early warning performance for MCI due to AD of this new method (areas under the curve (AUC) = 0.880) is better than that of the Minimum Mental State Examination (MMSE) neuropsychological scale (AUC = 0.856) assessed by physicians. Conclusion: Patients with MCI due to AD may have SEP disorders, and this new method based on dynamic evaluation of SEP will provide a novel human-computer interaction and intelligent early warning method for home and community screening of MCI due to AD.

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.

Dynamic contrast-enhanced ultrasonography with sonazoid predicts microvascular invasion in early-stage hepatocellular carcinoma.

OBJECTIVE: Microvascular invasion (MVI) is an independent risk factor for the early recurrence and poor survival of hepatocellular carcinoma (HCC). This study aims to investigate the potential clinical value of dynamic contrast-enhanced ultrasound (DCE-ultrasound)-Sonazoid in pre-operatively assessing MVI in HCC. METHODS AND MATERIALS: This single centre prospective study included 140 patients with histopathologically confirmed single HCC lesions. Patients were classified according to the post-operative pathological information presence of MVI: MVI+ group (n = 32) and MVI- group (n = 108). All patients underwent DCE-ultrasound within 1 week before surgery. The quantitative perfusion parameters of HCC lesions, margins of HCC lesions, and distal liver parenchyma were obtained and analyzed. RESULTS: Clinicopathological (serum alpha-fetoprotein, Des-gamma-carboxyprothrombin, and pathological grade) and grayscale imaging features (tumor size) were significantly different between the MVI+ and MVI- groups (p < 0.05). Further quantitative analysis showed that when comparing the MVI+ and MVI- groups, half-decrease time and wash-out rate of HCC lesions and peak enhancement in the arterial phase of difference between the margin area of HCC and distal liver parenchyma were significantly different (p = 0.045, p = 0.035, and p = 0.023, respectively). Combining the above three quantitative parameters, the accuracy, sensitivity, specificity, positive-predictive value, and negative-predictive value were 69.3% (97/140), 37.8% (17/45), 84.3% (80/95), 53.1% (17/32), 74.1% (80/108), respectively. CONCLUSION: DCE-ultrasound with quantitative perfusion analysis has the potential to predict MVI in HCC lesions. ADVANCES IN KNOWLEDGE: DCE-ultrasound with quantitative perfusion analysis has the potential to predict MVI in HCC lesions.

Rare variants confer shared susceptibility to gastrointestinal tract cancer risk.

Background: Cancers arising within the gastrointestinal tract are complex disorders involving genetic events that cause the conversion of normal tissue to premalignant lesions and malignancy. Shared genetic features are reported in epithelial-based gastrointestinal cancers which indicate common susceptibility among this group of malignancies. In addition, the contribution of rare variants may constitute parts of genetic susceptibility. Methods: A cross-cancer analysis of 38,171 shared rare genetic variants from genome-wide association assays was conducted, which included data from 3,194 cases and 1,455 controls across three cancer sites (esophageal, gastric and colorectal). The SNP-level association was performed by multivariate logistic regression analyses for single cancer, followed by association analysis for SubSETs (ASSET) to adjust the bias of overlapping controls. Gene-level analyses were conducted by SKAT-O, with multiple comparison adjustments by false discovery rate (FDR). Based on the significant genes indicated by SKATO analysis, pathways analysis was conducted using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Results: Meta-analysis in three gastrointestinal (GI) cancers identified 13 novel susceptibility loci that reached genome-wide significance (P ASSET< 5×10-8). SKAT-O analysis revealed EXOC6, LRP5L and MIR1263/LINC01324 to be significant genes shared by GI cancers (P adj<0.05, P FDR<0.05). Furthermore, GO pathway analysis identified significant enrichment of synaptic transmission and neuron development pathways shared by all three cancer types. Conclusion: Rare variants and the corresponding genes potentially contribute to shared susceptibility in different GI cancer types. The discovery of these novel variants and genes offers new insights for the carcinogenic mechanisms and missing heritability of GI cancers.

Genetic Modulation of BET1L Confers Colorectal Cancer Susceptibility by Reducing miRNA Binding and m6A Modification.

Genetic variants in regions encoding 3' untranslated regions (UTR) of mRNA potentially alter miRNA binding affinity and N6-methyladenosine (m6A) levels to affect gene expression. A better understanding of the association of these variants with colorectal cancer susceptibility could facilitate development of cancer prevention and treatment approaches. Here, we analyzed miRNA expression profiles and integrated genetic analyses from 8,533 individuals to evaluate the effects of altered miRNA-binding sites on colorectal cancer risk. The single-nucleotide polymorphism rs11245997 in the BET1L 3'UTR was significantly associated with colorectal cancer risk. The rs11245997 A allele facilitated BET1L expression by disrupting miR-140-3p binding. It also reduced BET1L m6A modification, which upregulated BET1L expression levels through a mechanism mediated by the m6A methyltransferases (METTL14 and WTAP) and the m6A demethylase ALKBH5. Moreover, higher expression of BET1L was associated with advanced tumor stages and poor patient prognosis. Increased BET1L expression promoted growth of colorectal cancer cells in vitro and in vivo, which could be partially rescued with miR-140-3p overexpression. RNA sequencing and pathway analyses indicated that BET1L is associated with the steroid biosynthesis pathway through regulation of HSD17B7, CYP27B1, and COMT. These findings provide insights into the involvement of genetic variants of BET1L in the development and progression of colorectal cancer. SIGNIFICANCE: The integration of miRNA expression profiles and genetic variants identified rs11245997 as a colorectal cancer risk-related variant that reduces miR-140-3p binding and m6A modification, leading to BET1L upregulation to promote colorectal tumorigenesis.

Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

Prognostic evaluation of polygenic risk score underlying pan-cancer analysis: evidence from two large-scale cohorts.

BACKGROUND: Polygenic risk score (PRS) has been demonstrated to be effective in identifying individuals at high risk of developing cancer, but its prognostic value remains unclear. METHODS: We constructed site-specific PRSs by aggregating the risk effect of independent variants derived from previous genome-wide association studies (GWASs) across 17 cancer types. The Cox proportional hazards model was used to evaluate the association of each PRS with cancer survival, leveraging data from two prospective European cohorts, namely the UK Biobank involving 19,628 incident cases and The Cancer Genome Atlas involving 7079 prevalent cases. The combined PRS (CPRS), determined by merging site-specific PRSs, was further used to assess the prognostic effect of PRS on overall cancer in a sex-specific manner. FINDINGS: We discovered that the cancer risk-related PRS was associated with neither overall survival (OS) nor cancer-specific survival (CSS) of each site-specific cancer with an underlying false discovery rate (FDR) P > 0.05, as evidenced by consistent findings from the two cohorts. Furthermore, the fixed-effect meta-analysis of the two cohorts provided no evidence to support for an association between CPRS and overall cancer survival in both males [OS: hazard ratio (HR)meta = 1.00, Pmeta = 0.760; CSS: HRmeta = 1.01, Pmeta = 0.447] and females (OS: HRmeta = 0.97, Pmeta = 0.067; CSS: HRmeta = 0.96, Pmeta = 0.054). Similar results were observed across multiple sensitivity analyses. INTERPRETATION: Our findings indicate that the risk-specific PRS might not be a clinically useful tool in cancer prognosis prediction and further studies focusing on the development of polygenic prognostic score are warranted. FUNDING: This project was funded by the National Natural Science Foundation of China (82173601 and 82073631), and Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).