Shared and distinct mechanisms of UBA1 inactivation across different diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance.

Predicting Lung Cancer in Korean Never-Smokers With Polygenic Risk Scores.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

A nested case-control study of untargeted plasma metabolomics and lung cancer among never-smoking women within the prospective Shanghai Women's Health Study.

The etiology of lung cancer in never-smokers remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Here, we aimed to enhance our understanding of lung cancer pathogenesis among never-smokers using untargeted metabolomics. This nested case-control study included 395 never-smoking women who developed lung cancer and 395 matched never-smoking cancer-free women from the prospective Shanghai Women's Health Study with 15,353 metabolic features quantified in pre-diagnostic plasma using liquid chromatography high-resolution mass spectrometry. Recognizing that metabolites often correlate and seldom act independently in biological processes, we utilized a weighted correlation network analysis to agnostically construct 28 network modules of correlated metabolites. Using conditional logistic regression models, we assessed the associations for both metabolic network modules and individual metabolic features with lung cancer, accounting for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 121 features inversely associated with all lung cancer (p = .001, FDR = 0.028) and lung adenocarcinoma (p = .002, FDR = 0.056), where lyso-glycerophospholipids played a key role driving these associations. Another module of 440 features was inversely associated with lung adenocarcinoma (p = .014, FDR = 0.196). Individual metabolites within these network modules were enriched in biological pathways linked to oxidative stress, and energy metabolism. These pathways have been implicated in previous metabolomics studies involving populations exposed to known lung cancer risk factors such as traffic-related air pollution and polycyclic aromatic hydrocarbons. Our results suggest that untargeted plasma metabolomics could provide novel insights into the etiology and risk factors of lung cancer among never-smokers.

Reproductive factors and risk of lung cancer among 300,000 Chinese female never-smokers: evidence from the China Kadoorie Biobank study.

BACKGROUND: Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. METHODS: The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004-2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. RESULTS: During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02-1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78-0.95) for > 12 months compared with those who breastfed for 7-12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. CONCLUSION: Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Risk-stratified Approach for Never- and Ever-Smokers in Lung Cancer Screening: A Prospective Cohort Study in China.

Rationale: Over 40% of lung cancer cases occurred in never-smokers in China. However, high-risk never-smokers were precluded from benefiting from lung cancer screening as most screening guidelines did not consider them. Objectives: We sought to develop and validate prediction models for 3-year lung cancer risks for never- and ever-smokers, named the China National Cancer Center Lung Cancer models (China NCC-LCm2021 models). Methods: 425,626 never-smokers and 128,952 ever-smokers from the National Lung Cancer Screening program were used as the training cohort and analyzed using multivariable Cox models. Models were validated in two independent prospective cohorts: one included 369,650 never-smokers and 107,678 ever-smokers (841 and 421 lung cancers), and the other included 286,327 never-smokers and 78,469 ever-smokers (503 and 127 lung cancers). Measurements and Main Results: The areas under the receiver operating characteristic curves in the two validation cohorts were 0.698 and 0.673 for never-smokers and 0.728 and 0.752 for ever-smokers. Our models had higher areas under the receiver operating characteristic curves than other existing models and were well calibrated in the validation cohort. The China NCC-LCm2021 ⩾0.47% threshold was suggested for never-smokers and ⩾0.51% for ever-smokers. Moreover, we provided a range of threshold options with corresponding expected screening outcomes, screening targets, and screening efficiency. Conclusion: The construction of the China NCC-LCm2021 models can accurately reflect individual risk of lung cancer, regardless of smoking status. Our models can significantly increase the feasibility of conducting centralized lung cancer screening programs because we provide justified thresholds to define the high-risk population of lung cancer and threshold options to adapt different configurations of medical resources.

Squamous Cell Carcinoma in Never Smokers: An Insight into SMARCB1 Loss.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Among NSCLCs, squamous cell carcinoma (SqCC) is strongly associated with smoking. However, lung cancer in never smokers (LCINS) represents approximately 25% of lung cancer cases globally and shows increasing incidence, particularly in East Asia. LCINS-SqCC is less well-characterized, especially regarding its genomic alterations and their impact on clinical outcomes. We conducted a retrospective analysis over a 20-year period (July 2003-July 2023) at two major tertiary centers in the UK. The cohort included 59 patients with LCINS-SqCC who underwent radical surgical resection. Data collected included demographic information, comorbidities, histopathological details, and outcome metrics such as disease-free and overall survival. Molecular sequencing of tumor specimens was performed to identify genomic aberrations. The cohort had a median age of 71 years (IQR 62-77) and a median BMI of 25.4 (IQR 22.8-27.8), with a slight male predominance (53%). The majority of patients (93%) had a preoperative MRC of 1-2. Recurrent disease was observed in 23 patients (39%), and 32 patients (54%) had died at a median follow-up of 3 years. Median disease-free survival was 545 days (IQR 132-1496), and overall survival was 888 days (IQR 443-2071). Preoperative creatinine levels were higher in patients who experienced recurrence (p = 0.037). Molecular analysis identified biallelic SMARCB1 loss in two younger patients, associated with rapid disease progression despite R0 resection. These patients' tumors were PDL1-negative, TTF-1-negative, and positive for cytokeratin, CD56, and p40. SMARCB1-deficient SqCC in never smokers represents a highly aggressive variant with poor disease-free survival, highlighting the importance of integrating advanced molecular diagnostics in clinical practice. This study underscores the necessity for personalized treatment strategies, including targeted therapies such as EZH2 inhibitors and immune checkpoint blockade, to address the unique molecular pathways in SMARCB1-deficient cancers. Further clinical trials are essential to optimize therapeutic approaches for this challenging subgroup of lung cancer.

Where there are fumes, there may be lung cancer: a systematic review on the association between exposure to cooking fumes and the risk of lung cancer in never-smokers.

PURPOSE: Lung cancer in never-smokers (LCINS) is the seventh leading cause of cancer, and exposure to cooking fumes has recently emerged as a potential risk factor. This systematic review is the first to summarize and evaluate the relationship between exposure to cooking fumes and the risk of LCINS. METHODS: This study conducted an online literature search of PubMed, CINAHL, and PsychInfo databases. Inclusion criteria were original research articles published in English, that assessed the relationship between exposure to cooking fumes and the risk of lung cancer between 1 January 2012 and 6 December 2022, and that included never-smokers. RESULTS: Thirteen case-control studies and three prospective cohort studies, focusing mostly on women with LCINS, met the inclusion criteria. Seven case-control studies reported an association between exposure to cooking oil fumes and an increased risk of LCINS. Two case-control studies found that using a fume extractor was associated with a decreased risk of LCINS. In other case-control studies, coal use was linked to an increased risk of LCINS, and participants who did not use a ventilator in their kitchens had a higher risk for LCINS. Poor ventilation [Adjusted Hazard Ratio (AHR) = 1.49; 95% CI: 1.15, 1.95] and poor ventilation in combination with coal use (AHR = 2.03; 95% CI: 1.35, 3.05) were associated with an increased risk for LCINS in one prospective cohort study. CONCLUSION: The evidence reviewed underscores the need to develop culturally-tailored interventions that improve access to affordable and clean fuel through engaging relevant stakeholders.

New insights into the biology and development of lung cancer in never smokers-implications for early detection and treatment.

Lung cancer is the leading cause of cancer deaths worldwide. Despite never smokers comprising between 10 and 25% of all cases, lung cancer in never smokers (LCNS) is relatively under characterized from an etiological and biological perspective. The application of multi-omics techniques on large patient cohorts has significantly advanced the current understanding of LCNS tumor biology. By synthesizing the findings of multi-omics studies on LCNS from a clinical perspective, we can directly translate knowledge regarding tumor biology into implications for patient care. Primarily focused on never smokers with lung adenocarcinoma, this review details the predominance of driver mutations, particularly in East Asian patients, as well as the frequency and importance of germline variants in LCNS. The mutational patterns present in LCNS tumors are thoroughly explored, highlighting the high abundance of the APOBEC signature. Moreover, this review recognizes the spectrum of immune profiles present in LCNS tumors and posits how it can be translated to treatment selection. The recurring and novel insights from multi-omics studies on LCNS tumor biology have a wide range of clinical implications. Risk factors such as exposure to outdoor air pollution, second hand smoke, and potentially diet have a genomic imprint in LCNS at varying degrees, and although they do not encompass all LCNS cases, they can be leveraged to stratify risk. Germline variants similarly contribute to a notable proportion of LCNS, which warrants detailed documentation of family history of lung cancer among never smokers and demonstrates value in developing testing for pathogenic variants in never smokers for early detection in the future. Molecular driver subtypes and specific co-mutations and mutational signatures have prognostic value in LCNS and can guide treatment selection. LCNS tumors with no known driver alterations tend to be stem-like and genes contributing to this state may serve as potential therapeutic targets. Overall, the comprehensive findings of multi-omics studies exert a wide influence on clinical management and future research directions in the realm of LCNS.

Evidence of Microplastics in Bronchoalveolar Lavage Fluid among Never-Smokers: A Prospective Case Series.

Microplastics (MPs) are abundant in air, but evidence of their deposition in the respiratory tract is limited. We conducted a prospective case series to investigate the deposition of microplastics in bronchoalveolar lavage fluid (BALF) and determine the internal dose of MPs via inhalation. Eighteen never-smokers aged 32-74 years who underwent fiberoptic bronchoscopy with BALF were recruited from Zhuhai, China. Control samples were obtained by performing the same procedure using isotonic saline instead of BALF. Laser direct infrared spectroscopy combined with scanning electron microscopy detected the presence and characteristics of MPs and quantitatively analyzed the microplastic in BALF and control samples. Concentrations of total and specific MPs in BALF and control samples were compared using the Wilcox test. Thirteen types of MPs were observed in 18 BALF samples. Polyethylene (PE, 86.1%) was the most abundant in BALF, followed by poly(ethylene terephthalate) (PET, 7.5%) and polypropylene (PP, 1.9%). Compared with the control samples, BALF had significantly higher concentrations of PE (median [IQR] of BALF: 0.38 [8.05] N/g), PET (0.26 [0.54] N/g), polyurethane (0.16 [0.24] N/g), PP (0.16 [0.11] N/g), and total MPs (0.91 [6.58] N/g). The presence of MPs in BALF provides novel evidence that MPs penetrate deep into the respiratory tract.

Lung cancer risk and exposure to air pollution: a multicenter North China case-control study involving 14604 subjects.

BACKGROUND: For North Chinese lung cancer patients, there is limited study on the distribution of air pollution and smoking related features based on analyses of large-scale, high-quality population datasets. The aim of the study was to fully analyze risk factors for 14604 Subjects. METHODS: Participants and controls were recruited in 11 cities of North China. Participants' basic information (sex, age, marital status, occupation, height, and weight), blood type, smoking history, alcohol consumption, history of lung-related diseases and family history of cancer were collected. PM2.5 concentration data for each year in each city of the study area from 2005 to 2018 were extracted based on geocoding of each person's residential address at the time of diagnosis. Demographic variables and risk factors were compared between cases and matched controls using a univariate conditional logistic regression model. Multivariate conditional logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for risk factors in univariate analysis. The nomogram model and the calibration curve were developed to predict lung cancer probability for the probability of lung cancer. RESULTS: There was a total of 14604 subjects, comprising 7124 lung cancer cases and 7480 healthy controls included in the study. Marital status of unmarried persons, people with a history of lung-related disease, corporate personnel and production /service personnel were protective factors for lung cancer. People younger than 50 years old, people who were smoking and quit smoking, people who had been drinking consistently, people with family history of cancer and PM2.5 exposure were proven to be a risk factor for lung cancer. The risk of lung cancer varied with sex, smoking status and air pollution. Consistent alcohol consumption, persistent smoking and smoking quit were risk factors for lung cancer in men. By smoking status, male was risk factor for lung cancer in never smokers. Consistent alcohol consumption added risk for lung cancer in never smokers. The combined effects of PM2.5 pollution exposure and ever smoking aggravated the incidence of lung cancer. According to air pollution, lung cancer risk factors are completely different in lightly and heavily polluted areas. In lightly polluted areas, a history of lung-related disease was a risk factor for lung cancer. In heavily polluted areas, male, consistent alcohol consumption, a family history of cancer, ever smokers and smoking quit were all risk factors for lung cancer. A nomogram was plotted and the results showed that PM2.5 was the main factor affecting the occurrence of lung cancer. CONCLUSIONS: The large-scale accurate analysis of multiple risk factors in different air quality environments and various populations, provide clear directions and guidance for lung cancer prevention and precise treatment.