Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.

High-throughput characterization of functional variants highlights heterogeneity and polygenicity underlying lung cancer susceptibility.

Genome-wide association studies (GWASs) have identified numerous lung cancer risk-associated loci. However, decoding molecular mechanisms of these associations is challenging since most of these genetic variants are non-protein-coding with unknown function. Here, we implemented massively parallel reporter assays (MPRAs) to simultaneously measure the allelic transcriptional activity of risk-associated variants. We tested 2,245 variants at 42 loci from 3 recent GWASs in East Asian and European populations in the context of two major lung cancer histological types and exposure to benzo(a)pyrene. This MPRA approach identified one or more variants (median 11 variants) with significant effects on transcriptional activity at 88% of GWAS loci. Multimodal integration of lung-specific epigenomic data demonstrated that 63% of the loci harbored multiple potentially functional variants in linkage disequilibrium. While 22% of the significant variants showed allelic effects in both A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cell lines, a subset of the functional variants displayed a significant cell-type interaction. Transcription factor analyses nominated potential regulators of the functional variants, including those with cell-type-specific expression and those predicted to bind multiple potentially functional variants across the GWAS loci. Linking functional variants to target genes based on four complementary approaches identified candidate susceptibility genes, including those affecting lung cancer cell growth. CRISPR interference of the top functional variant at 20q13.33 validated variant-to-gene connections, including RTEL1, SOX18, and ARFRP1. Our data provide a comprehensive functional analysis of lung cancer GWAS loci and help elucidate the molecular basis of heterogeneity and polygenicity underlying lung cancer susceptibility.

Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom.

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear. Methods: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations. Results: Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases. Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Epigenome-wide association study of lung cancer among never smokers in two prospective cohorts in Shanghai, China.

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted. METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse samples using Illumina MethylationEPIC array. Initially, we conducted an EWAS to identify differentially methylated positions (DMPs) associated with lung cancer in the discovery sample of 101 subjects. The top 50 DMPs were further evaluated in a replication sample of 62 subjects, and results were pooled using fixed-effect meta-analysis. RESULTS: Our study identified three DMPs significantly associated with lung cancer at the epigenome-wide significance level of p<8.22×10-8. These DMPs were identified as cg09198866 (MYH9; TXN2), cg01411366 (SLC9A10) and cg12787323. Furthermore, examination of the top 1000 DMPs indicated significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways. Additionally, GrimAge acceleration was identified as a risk factor for lung cancer (OR=1.19 per year; 95% CI 1.06 to 1.34). CONCLUSIONS: While replication in a larger sample size is necessary, our findings suggest that DNAm patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never smokers.

The mutagenic forces shaping the genomic landscape of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock-Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR-mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10-5), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10-5). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

APOBEC shapes tumor evolution and age at onset of lung cancer in smokers.

APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues1,2. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B)3-6. However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence7, apoptosis8, and cell regeneration9, as indicated by high expression of pulmonary healing signaling pathway, stemness markers and distal cell-of-origin in HAS. The expected association of tobacco smoking variables (e.g., time to first cigarette) with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS have more neoantigens, slower clonal expansion, and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells and frequent immuno-editing. These findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development, with important clinical implications.

Association of oral microbiome with oral human papillomavirus infection: a population study of the National Health and Nutrition Examination Survey, 2009-2012.

BACKGROUND: Oral human papillomavirus(HPV) infection and the oral microbiome are associated with oropharyngeal cancer. However, population-based data on the association of oral microbiome with oral HPV infection are limited. METHOD: We performed a cross-sectional analysis of 5,496 participants aged 20-59 in National Health and Nutrition Examination Surveys(NHANES):2009-2012. The association between either oral microbiome alpha diversity or beta diversity and oral HPV infection was assessed using multivariable logistic regression or principal coordinate analyses(PCoA) and multivariate analysis of variance(PERMANOVA). RESULTS: For alpha diversity, we found a lower number of observed Amplicon sequence variants(ASVs) (adjusted odds ratio[aOR] = 0.996; 95%CI = 0.992-0.999) and reduced Faith's Phylogenetic Diversity(aOR = 0.95; 95%CI = 0.90-0.99) associated with high-risk oral HPV infection in the overall population. This trend was observed in males for both high-risk and any oral HPV infection. Beta diversity showed differentiation of oral microbiome community by high-risk oral HPV infection as measured by Bray-Curtis dissimilarity (R2 = 0.054%; P = .029) and unweighted UniFrac distance (R2 = 0.046%; P = .045) among the overall population, and associations were driven by males. CONCLUSIONS: Both oral microbiome alpha diversity(within-sample richness and phylogenetic diversity) and beta diversity(heterogeneous dispersion of oral microbiome community) are associated with HPV infection. Longitudinal studies are needed to characterize the role of the microbiome in the natural history of oral HPV infection.

Phenotypic and genetically predicted leucocyte telomere length and lung cancer risk in the prospective UK Biobank.

We investigated phenotypic leucocyte telomere length (LTL), genetically predicted LTL (gTL), and lung cancer risk among 371 890 participants, including 2829 incident cases, from the UK Biobank. Using multivariable Cox regression, we found dose-response relationships between longer phenotypic LTL (p-trendcontinuous=2.6×10-5), longer gTL predicted using a polygenic score with 130 genetic instruments (p-trendcontinuous=4.2×10-10), and overall lung cancer risk, particularly for adenocarcinoma. The associations were prominent among never smokers. Mendelian Randomization analyses supported causal associations between longer telomere length and lung cancer (HRper 1 SD gTL=1.87, 95% CI: 1.49 to 2.36, p=4.0×10-7), particularly adenocarcinoma (HRper 1 SD gTL=2.45, 95%CI: 1.69 to 3.57, p=6.5×10-6).

Pan-cancer mutational signature analysis of 111,711 targeted sequenced tumors using SATS.

Tumor mutational signatures have the potential to inform cancer diagnosis and treatment. However, their detection in targeted sequenced tumors is hampered by sparse mutations and variability in targeted gene panels. Here we present SATS, a scalable mutational signature analyzer addressing these challenges by leveraging tumor mutational burdens from targeted gene panels. Through analyzing simulated data, pseudo-targeted sequencing data generated by down-sampling whole exome and genome data, and samples with matched whole genome sequencing and targeted sequencing, we showed that SATS can accurately detect common mutational signatures and estimate signature burdens. Applying SATS to 111,711 targeted sequenced tumors from the AACR Project GENIE, we generated a pan-cancer catalogue of mutational signatures tailored to targeted sequencing, enabling estimation of signature burdens within individual tumors. Integrating signatures with clinical data, we demonstrated SATS's clinical utility, including identifying signatures enriched in early-onset hypermutated colorectal cancers and signatures associated with cancer prognosis and immunotherapy response.

Real-time, random-access organ screening for carbapenem-resistant organisms (CRO) reduces CRO-associated, donor-derived infection mortality in lung transplant recipients.

PURPOSE: Donor-derived infection (DDI) has become an important factor affecting the prognosis of lung transplantation patients. The risks versus benefits of using donor organs infected with multidrug-resistant organisms (MDRO), especially carbapenem-resistant organisms (CRO), are frequently debated. Traditional microbial culture and antimicrobial susceptibility testing at present fail to meet the needs of quick CRO determination for donor lungs before acquisition. In this study, we explored a novel screening method by using Xpert® Carba-R assay for CRO in donor lungs in a real-time manner to reduce CRO-associated DDI mortality. METHODS: This study was registered on chictr.org.cn (ChiCTR2100053687) on November 2021. In the Xpert Carba-R screening group, donor lungs were screened for CRO infection by the Xpert Carba-R test on bronchoalveolar fluid (BALF) before acquisition. If the result was negative, donor lung acquisition and subsequent lung transplantation were performed. In the thirty-five potential donors, nine (25.71%) with positive Xpert Carba-R results in BALF were declined for lung transplantation. Twenty-six recipients and the matching CRO-negative donor lungs (74.29%) were included in the Xpert Carba-R screening group. In the control group, nineteen recipients underwent lung transplants without Xpert Carba-R screening. The incidence and mortality of CRO-associated DDI were collected and contrasted between the two groups. RESULTS: Multivariate analysis showed that CRO-related death due to DDI within 60 days was significantly lower in the Xpert Carba-R screening group than that in the control group (OR = 0.05, 95% CI 0.003-0.74, p = 0.03). CONCLUSION: Real-time CRO screening of donor lungs before transplantation at the point of care by the Xpert Carba-R helps clinicians formulate lung transplantation strategies quickly and reduces the risk of subsequent CRO infection improving the prognosis of lung transplantation.

Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomization analysis.

BACKGROUND: People with cancer experience high rates of venous thromboembolism (VTE). Risk of subsequent cancer is also increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. METHODS: We used data from large genome-wide association study meta-analyses to perform bidirectional Mendelian randomization analyses to estimate causal associations between genetic liability to VTE and risk of 18 different cancers. RESULTS: We found no conclusive evidence that genetic liability to VTE was causally associated with an increased incidence of cancer, or vice versa. We observed an association between liability to VTE and pancreatic cancer risk [odds ratio for pancreatic cancer: 1.23 (95% confidence interval: 1.08-1.40) per log-odds increase in VTE risk, P = 0.002]. However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence to suggest a causal relationship. CONCLUSIONS: These findings do not support the hypothesis that genetic liability to VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesize evidence for these mechanisms.

Polygenic Risk Score, Environmental Tobacco Smoke, and Risk of Lung Adenocarcinoma in Never-Smoking Women in Taiwan.

Importance: Estimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs. Objectives: To integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan. Design, Setting, and Participants: The analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022. Exposures: A PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work. Main Outcomes and Measures: The Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure. Results: Data were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified. Conclusions and Relevance: This study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

Uncovering the complex relationship between balding, testosterone and skin cancers in men.

Male-pattern baldness (MPB) is related to dysregulation of androgens such as testosterone. A previously observed relationship between MPB and skin cancer may be due to greater exposure to ultraviolet radiation or indicate a role for androgenic pathways in the pathogenesis of skin cancers. We dissected this relationship via Mendelian randomization (MR) analyses, using genetic data from recent male-only meta-analyses of cutaneous melanoma (12,232 cases; 20,566 controls) and keratinocyte cancers (KCs) (up to 17,512 cases; >100,000 controls), followed by stratified MR analysis by body-sites. We found strong associations between MPB and the risk of KC, but not with androgens, and multivariable models revealed that this relationship was heavily confounded by MPB single nucleotide polymorphisms involved in pigmentation pathways. Site-stratified MR analyses revealed strong associations between MPB with head and neck squamous cell carcinoma and melanoma, suggesting that sun exposure on the scalp, rather than androgens, is the main driver. Men with less hair covering likely explains, at least in part, the higher incidence of melanoma in men residing in countries with high ambient UV.

Associations between Longer Leukocyte Telomere Length and Increased Lung Cancer Risk among Never Smokers in Urban China.

BACKGROUND: The complex relationship between measured leukocyte telomere length (LTL), genetically predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology. METHODS: To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's Health Studies (798 cases and 792 controls) and Shanghai Men's Health Studies (161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the ORs and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. In addition, we conducted Mendelian randomization (MR) using MR-PRESSO. RESULTS: We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (P trendLTL = 4×10-6; P trendgTL = 3×10-4). Similarly, among never-smoking men, longer measured LTL was associated with over triple the risk compared with those with the shortest (OR, 3.48; 95% CI, 1.85-6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL, 1.19; 95% CI, 1.03-1.37; P = 0.03). CONCLUSIONS: Longer pre-diagnostic LTL is associated with increased lung cancer risk among never smokers. IMPACT: Our findings firmly support the role of longer telomeres in lung carcinogenesis.

Causal relationships between risk of venous thromboembolism and 18 cancers: a bidirectional Mendelian randomisation analysis.

Background: People with cancer experience high rates of venous thromboembolism (VTE). Additionally, risk of subsequent cancer is increased in people experiencing their first VTE. The causal mechanisms underlying this association are not completely understood, and it is unknown whether VTE is itself a risk factor for cancer. Methods: We used data from large genome-wide association study meta-analyses to perform bi-directional Mendelian randomisation analyses to estimate causal associations between genetically-proxied lifetime risk of VTE and risk of 18 different cancers. Results: We found no conclusive evidence that genetically-proxied lifetime risk of VTE was causally associated with an increased incidence of cancer, or vice-versa. We observed an association between VTE and pancreatic cancer risk (odds ratio for pancreatic cancer 1.23 (95% confidence interval 1.08 - 1.40) per log-odds increase in risk of VTE, P = 0.002). However, sensitivity analyses revealed this association was predominantly driven by a variant proxying non-O blood group, with inadequate evidence from Mendelian randomisation to suggest a causal relationship. Conclusions: These findings do not support the hypothesis that genetically-proxied lifetime risk of VTE is a cause of cancer. Existing observational epidemiological associations between VTE and cancer are therefore more likely to be driven by pathophysiological changes which occur in the setting of active cancer and anti-cancer treatments. Further work is required to explore and synthesise evidence for these mechanisms.

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Osthole relieves skin damage and inhibits chronic itch through modulation of Akt/ZO-3 pathway in atopic dermatitis.

Atopic dermatitis (AD) is the most prevalent chronic inflammatory skin condition and significantly reduces quality of life. Tight junction (TJ), which is located directly beneath the stratum corneum, maintains skin barrier function and aids in the identification of the cell's "territory". We evaluated seventeen TJ related genes to explore AD related alterations of TJ. Remarkably, we found that the expression of ZO-3, a gene that had not been linked to the development of TJ in AD, was significantly down-regulated in the skin of AD mice and patients. siRNA mediated knock-down of ZO-3 significantly decreased transepithelial electrical resistance in HaCaT cells, demonstrating that ZO-3 is essential to epidermal barrier function. In addition to ZO-3 downregulation, protein kinase B (Akt) phosphorylation was increased in the skin of AD mice. We further confirmed an inverse relationship between Akt phosphorylation and ZO-3 expression in AD using HaCaT cells and mouse model. Finally, we tested the efficacy of osthole as a treatment for AD in mice and HaCaT cells. Osthole inhibits Akt phosphorylation, and thereby enhances ZO-3 expression in mouse models of AD, resulting in greatly lessened AD associated skin damage and chronic itch, and osthole also increased the expression of ZO-3 in HaCaT cells by inhibiting the phosphorylation of Akt. Together, we established that ZO-3 is essential for the development of TJ in AD skin and HaCaT cells, and our findings provide fresh support for osthole's ability to protect ZO-3 expression and the epidermal barrier in AD.

Stability of the Fecal and Oral Microbiome over 2 Years at -80°C for Multiple Collection Methods.

BACKGROUND: In prospective cohorts, biological samples are generally stored over long periods before an adequate number of cases have accrued. We investigated the impact of sample storage at -80°C for 2 years on the stability of the V4 region of the 16S rRNA gene across seven different collection methods (i.e., no additive, 95% ethanol, RNAlater stabilization solution, fecal occult blood test cards, and fecal immunochemical test tubes for feces; OMNIgene ORAL tubes and Scope mouthwash for saliva) among 51 healthy volunteers. METHODS: Intraclass correlation coefficients (ICC) were calculated for the relative abundance of the top three phyla, the 20 most abundant genera, three alpha-diversity metrics, and the first principal coordinates of three beta-diversity matrices. RESULTS: The subject variability was much higher than the variability introduced by the sample collection type, and storage time. For fecal samples, microbial stability over 2 years was high across collection methods (range, ICCs = 0.70-0.99), except for the samples collected with no additive (range, ICCs = 0.23-0.83). For oral samples, most microbiome diversity measures were stable over time with ICCs above 0.74; however, ICCs for the samples collected with Scope mouthwash were lower for two alpha-diversity measures, Faith's phylogenetic diversity (0.23) and the observed number of operational taxonomic units (0.23). CONCLUSIONS: Fecal and oral samples in most used collection methods are stable for microbiome analyses after 2 years at -80°C, except for fecal samples with no additive. IMPACT: This study provides evidence that samples stored for an extended period from prospective studies are useful for microbiome analyses.