Impact of LMNA gene polymorphism (rs581342) on lung cancer susceptibility: Evidence from a southeast Iranian population

Inherited genomic susceptibility and associated transcriptomic patterns are crucial players in lung cancer etiology. Lung cancer susceptibility is getting rising attention in carcinogenesis. The present study aimed to investigate unique clinical features and transcriptomic profile in patients with familial lung cancer (FLC) in Yunnan-Guizhou Plateau, Wumeng-Mountain area of China. 1,823 local lung cancer patients were enrolled (762 FLC, 1061 Sporadic). Clinicopathologic parameters were analyzed and summarized. 43 lung tissue samples (the adjacent nonmalignant tissue) were selected for Transcriptome/RNA-seq, the differential gene expression patterns were analyzed, significant functions and pathways were enriched and studied. Our FLC cohort showed unique characters: younger age; increased rate of adenocarcinoma, and early-stage cases; unbalance in blood types, anatomic sites and co-existing diseases; highlighted with significantly elevated comorbidity and early-onset of hypertension in FLC + population. Notably, our FLC + group exhibited a higher rate of bilateral lung cancers and multiple pulmonary nodules; beside, were more likely to develop different cysts, polyps, hyperplasia at a younger age. The transcriptome found that immune-related functions & pathways were significantly enriched in the familial cohort. E.g. "immune cells recruitment" with higher Neutrophils/ lower CD4 memory T cells. Collectively, these transcriptomic differences suggested: individuals with FLC may have baseline alterations in immune regulation, which could reflect a compromised immune surveillance or dysregulated inflammatory tone in their normal lung tissue. For the key gene, MUC16 may contribute to this process by influencing the assembly, structure & dynamical functions of pulmonary epithelial cilium; which could potentially impair mucociliary clearance, leading to prolonged retention of pollutants and carcinogens in the lung microenvironment. Hereditary factors likely contribute to the susceptibility to both lung cancer and hypertension in this population, while chronic exposure to local air pollution may further promote their early-onset and comorbidity. Our findings highlighted the potential significance of MUC16 in familial lung cancer or even early-onset lung cancer; and provided useful data for early screening and personalized treatment strategies for lung cancer.

Lung cancer remains the leading cause of cancer-related deaths worldwide, with limited genetic data available on Middle Eastern populations. This study investigated four novel genetic variants CYPHER rs7834621, METOX1 rs9284659, DRUGRES2 rs4521739, and TOXMET3 rs8823471 for their association with lung cancer risk and treatment response in Iraqi patients. Between January 2024 and September 2024, we recruited 265 tissue-confirmed lung cancer patients and 310 healthy controls from Al-Diwaniyah Teaching Hospital. DNA was extracted from blood samples and genotyped using tetra-ARMS-PCR. Logistic regression was used to analyze variant-cancer risk associations. Pharmacogenetic analysis included 198 patients receiving trastuzumab, doxorubicin, paclitaxel, and cyclophosphamide chemotherapy, with response measured by RECIST criteria. All four genetic variants showed significant associations with lung cancer risk. The CYPHER rs7834621 GG genotype was associated with the highest disease risk (adjusted OR = 2.21, 95% CI: 1.31-3.73, p = 0.003). Allele frequencies were population-specific when compared to other cohorts. Pharmacogenetic analysis revealed treatment response associations, with DRUGRES2 rs4521739 TT genotype demonstrating superior response rates compared to CC genotype (68.4% vs 31.6%, p < 0.001). Haplotype analysis identified specific gene combinations that increased disease susceptibility. These novel SNPs are associated with both lung cancer risk and treatment response in Iraqi patients, potentially serving as biomarkers for risk stratification and personalized therapy guidance in this population.

Epigenetic factors underlying telomere length (TL) may provide insight into telomeric homeostasis, with direct links to cigarette smoking and lung cancer susceptibility. It is unclear, nevertheless, to what extent effects of TL and its related DNA methylation on the smoking-induced lung tumorigenesis. A case-cohort study is performed within the Dongfeng-Tongji (DFTJ) cohort, including a randomly selected subcohort of 1399 subjects and 359 incident lung cancer cases. We use a linear regression model to conduct EWAS of TL, while the associations of TL and candidate CpGs with lung cancer risk are evaluated using weighted Cox proportional hazard regression models. Furthermore, the causal inference test (CIT) and mediation analysis are used to elucidate the causality of TL and its relevant CpGs in the smoking-induced lung tumorigenesis. The methylation-expression associations are assessed in SY panel (n = 144), adjacent normal lung tissues (n = 32) and solid normal tissues in TCGA (n = 375). We identified 31 CpGs with significant associations with TL at FDR < 0.05, and their annotated genes are mainly enriched in oxidative stress, energy metabolism and immunity regulation pathways. Among the 31 TL-related CpGs, 3 CpGs showed substantial associations with both lung cancer risk and smoking status (all FDR < 0.1), including cg26563141 in RGPD1/RGPD2, cg03964851in MIR1974/KIAA0825, and cg08976633 in ZNF74. The further mediation analyses suggest that these three CpGs could mediate 2.89%~8.83% effect on lung cancer risk induced by smoking (all FDR < 0.1). The further CIT and multiple mediation analysis reveal that the effect of smoking on lung cancer risk is primarily mediated by TL (> 10%) while being mildly mediated via DNA methylation pathway (< 1%). Also, hypermethylation of cg26563141 is related to low expression of RGPD1 and RGPD2 across blood and tissue samples. Both TL attrition and the three candidate CpGs showed significant mediation effects on lung cancer risk induced by smoking. These findings provide novel insight into the epigenetic control of telomere homeostasis mechanisms and clues for methylation alteration and TL in smoking-induced lung tumorigenesis.

Genome-wide DNA methylation profiling reveals body mass Index-dependent epigenetic signatures associated with lung cancer susceptibility.

Seasonal biomass-burning haze in Northern Thailand produces sharp fluctuations in ambient fine particulate matter (PM), posing heightened health risks, particularly for individuals with diabetes mellitus (DM). To identify PM-responsive biomarkers and assess whether metabolic status modifies these responses, we first performed small RNA sequencing in a discovery cohort using plasma samples collected during low- and high-PM periods. Thirteen circulating microRNAs (miRNAs) were differentially expressed, including reduced miR-542-3p and elevated miR-29a-3p, novelmiR-203, and novelmiR-754, with predicted targets enriched in immune and endoplasmic-reticulum stress pathways. These four miRNAs were quantified by RT-qPCR in a longitudinal cohort of adults with (n = 28) and without DM (n = 29) sampled at three PM-defined timepoints across one full haze cycle. In non-DM individuals, miR-542-3p decreased at peak exposure while miR-29a-3p and novelmiR-203 increased, with values returning toward baseline at re-exposure. DM participants showed altered baseline levels and attenuated or reversed seasonal changes. Plasma IL-8 rose markedly at peak PM in both groups, mirroring exosome concentration increases measured by NTA, indicating a transient systemic inflammatory response. In an independent clinical cohort, only miR-542-3p differed significantly between lung-cancer patients and healthy controls. These findings indicate that PM exposure reconfigures circulating miRNA, exosomal, and cytokine profiles, and that DM modifies these responses, highlighting miR-542-3p and miR-29a-3p as environmentally responsive and disease-relevant biomarker candidates.

Plasma proteins significantly influence the pathogenesis and progression of Lung cancer (LC). However, research examining the plasma protein-to-protein ratios (rQTL) in LC is limited. Mendelian randomization (MR) uses genetic variants as instrumental variables to infer causal relationships between exposures and outcomes, minimizing confounding and reverse causation. The rQTL approach captures biologically meaningful protein-protein interactions and pathway-level regulation that may be missed when studying individual proteins. We performed a two-sample MR analysis by using summary statistics to investigate the causal relationship between rQTLs and LC risk. Reverse MR analysis confirmed unidirectional causality. Additionally, Bayesian and Susie colocalization analyses were conducted to assess the strength of causal relationships, whereas linkage disequilibrium score regression (LDSC) genetic scores were used to examine the robustness of the genetic associations. The discovery cohort identified 20 significant rQTLs associated with LC risk after false discovery rate correction, with the strongest effects observed for: DNAJA2/SCAMP3 (OR = 0.66, 95% CI, 0.54–0.81), CNST/MAVS (OR = 1.40, 95% CI, 1.05–1.88), whereas the LDSC genetic score for DNAJA2/SCAMP3 and DSC2/SPINT1 exhibited statistical significance. Replication confirmed CNST/MAVS (OR = 1.002, 95% CI, 0.993–1.007) and four additional rQTLs (BSG/TNFRSF4, AXIN1/HEXIM1, BIN2/F11R, and CDC27/CEP85). Sensitivity analyses confirmed no evidence of pleiotropy and robust causal estimates. This study provides genetic evidence supporting causal roles for specific plasma protein ratios in LC susceptibility. These findings highlight the value of protein ratio-based biomarkers and suggest potential targets for further mechanistic and clinical investigation. The identified rQTLs may contribute to improved risk prediction and therapeutic strategies for LC.

Introduction: High-mobility group box 1 (HMGB1) protein plays a significant role in cancer development and treatment response. The current research on the role of HMGB1 in lung cancer and its treatment outcomes is limited and inconsistent. This exploratory study investigated the association between HMGB1 common genetic variants and lung cancer susceptibility, as well as cisplatin chemotherapy response, in a Chinese cohort. Methods: The current study included 106 individuals diagnosed with lung cancer and 93 healthy subjects, all of whom were part of a Chinese population cohort. HMGB1 polymorphisms (rs1045411, rs1412125, rs2249825, and rs1360485) were genotyped using the TaqMan single-nucleotide polymorphism typing method. HMGB1 gene expression in the lung tissue of patients was quantified using real-time PCR. All patients were administered cisplatin, and their response to the drug was evaluated. All statistical analyses were performed using GraphPad Prism v10. Results: The control group exhibited a higher frequency of heterozygous variants for HMGB1 polymorphisms rs1045411 (p = 0.01, odds ratio [OR] = 0.45) and rs1412125 (p = 0.03, OR = 0.46) than the patients. Moreover, the combined mutant genotypes for HMGB1 rs1045411 (p = 0.0001, OR = 0.15) and rs2249825 (p = 0.003, OR = 0.19) exhibited favorable responses to cisplatin treatment. Moreover, the wild-type variants of rs1045411 and rs2249825 exhibited higher HMGB1 expression than the mutants; however, this difference was not statistically significant. Conclusion: This preliminary investigation indicated potential associations between HMGB1 genetic variants and lung cancer susceptibility and treatment response. These exploratory findings necessitate further validation through larger multicenter studies incorporating functional assays to elucidate the biological significance and clinical utility of HMGB1 polymorphisms in the management of lung cancer.

Single-cell eQTL mapping reveals cell-type-specific genetic regulation in lung cancer.

DNA damage and repair (DDR) mechanisms are crucial for maintaining genomic stability by counteracting genetic insults that occur continuously in living organisms. Impairments in DDR pathways can lead to the accumulation of mutations and contribute to carcinogenesis. Lung cancer (LC) remains one of the most prevalent and lethal malignancies worldwide, affecting both men and women. This study aimed to investigate the association between the RAD51 -4719A/T (rs2619679) single nucleotide polymorphism (SNP) and lung cancer susceptibility. It also examined the correlation between RAD51 SNP genotypes and demographic, clinical, and pathological features in a cohort of Iraqi patients. This case-control study consisted of fifty healthy individuals and one hundred and five lung cancer patients. Genotyping of the RAD51 gene -4719A/T polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Lung cancer was significantly more frequent among older patients (aged 60-69 years), males, and smokers (p ≤ 0.01). A statistically significant association was found between the RAD51 -4719A/T polymorphism and lung cancer risk. Individuals carrying the AT and TT genotypes were observed to have a significantly higher frequency of lung cancer compared to those with the AA genotype, highlighting the potential role of this polymorphism in disease susceptibility (χ² =127.68, p =0.00000001). Furthermore, the T allele of this SNP was found to be significantly more frequent in lung cancer patients than in controls (p = 0.00000001), suggesting a potential role in increased genetic susceptibility to lung cancer. This study is among the first to investigate the -4719A/T (rs2619679) polymorphism in the RAD51 gene and its association with lung cancer in the Iraqi population. A statistically significant association was identified between this variant and lung cancer risk. The genotypic patterns identified suggest that the presence of the T allele particularly in the more frequently occurring heterozygous AT genotype may contribute to the molecular mechanisms involved in lung cancer development through its impact on DNA repair processes.

It has been observed that lung cancer patients are more susceptible to COVID-19. Establishing the causal relationships between lung cancer and COVID-19 susceptibility and severity is challenging due to numerous confounding factors. Mendelian randomization (MR) is an effective method to investigate the causal association between exposure and outcome variables. However, different studies have yielded conflicting conclusions regarding the role of lung cancer in COVID-19 susceptibility and severity. Lung cancer subtypes exhibit heterogeneity in genetic susceptibility, which may influence the assessment of the true relationship between lung cancer and COVID-19 susceptibility and severity. In this study, we utilized the most recent COVID-19 association data from The COVID-19 Host Genetics Initiative with more than two million samples in total, in combination with genetic data of different lung cancer subtypes with more than eighty-five thousand samples, and conducted a two-sample Mendelian randomization study. We examined the associations between lung cancer and its four subtypes with COVID-19 susceptibility, hospitalization, and severity. Our data indicates that lung cancer, overall, does not have a causal association with COVID-19 susceptibility, hospitalization, or severity. However, lung cancer in ever smokers is nominally associated with COVID-19 hospitalization p-value 0.035, false discover rate (FDR) q = 0.14 and increased severity p = 0.032, q = 0.04. Additionally, small cell lung carcinoma is associated with increased COVID-19 severity p = 0.011, q = 0.04.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-15239-w.

BackgroundSingle nucleotide variants are important factors involved in lung cancer onset and prognosis. In Cuba, there are scarce studies evaluating the possible association between genetic variants and lung cancer. Here, we described the frequency distribution of genetic variants in DNA repair related genes and assessed their impact on lung cancer susceptibility and survival prognosis in a cohort of Cuban populationMethodsCase-Control study included 300 lung cancer patients and 300 control subjects. Variants: rs1042522, rs11016879, rs13181, rs25487 and rs861539 were genotyped. The association analysis was evaluated by logistic regression and the impact on overall survival was estimated by Kaplan-Meier and Cox regression analyses. ResultsGenotype frequencies were in Hardy-Weinberg equilibrium except for rs1042522 in patients. The heterozygote of this variant was associated with low risk to lung cancer (Overdominant, OR: 0.53, p = 0.01). Conversely, rs25487 showed trend to additive genotype risk (Additive model, OR:1.61, p = 0.01). Differences in genotype frequencies according to skin color of controls were detected for rs1042522 and rs861539 (p = 0.01). The rs11016879 and rs1042522 showed joint protective effects with skin color. Interaction between rs25487 and cigarette smoking analysis revealed higher lung cancer risk (OR = 3.72, p = 0.03, p-interaction: 0.01). Interaction between alcohol consumption and rs13181 reached borderline significance for decreased risk of lung cancer (OR = 0.25, p = 0.03, p-interaction: 0.06). In addition, rs11016879 alternative allele was an independent factor for higher mean 5-years overall survival (log-rank test p = 0.03). ConclusionsThe study provides the first data evaluating the relevance of genetic variants in DNA damage repair related genes for lung cancer management in Cuban population. Our findings indicate a significant contribution of the genetic variants to lung cancer susceptibility and highlights the importance of considering skin color within analyses for disease susceptibility in Cuban population.

Abstract Description For decades there has been an alarming increase in lung cancer in never smoker (LCINS) that occurs more frequently in young women. Pulmonary macrophages (pMac) play a key role in lung cancer (LC) development and are heavily influenced by sex chromosomes and gonadal hormones. We hypothesize that the pMac response to environmental respiratory hazards (ERHs) is sex-specific and results in divergent immunopathology and susceptibility to LCINS. Using EPA and satellite data, we compared modeled particulate matter ≤2.5µm (PM2.5) exposure levels in 2,944 at-risk patients. Women with high PM2.5 exposures had twice the risk of developing LC compared to men. Spatial transcriptomics was performed on tumors from 15 female and 5 male LCINS patients. Female pMacs expressed pathways promoting tissue remodeling, growth factor signaling, and catabolic metabolism compared to male pMacs which regulated interferon signaling, ROS production, and antigen processing-cross presentation. Compared to males, female FVB/N mice exposed to aerosolized ERHs for 4wks amassed pMacs in the lung. Female pMacs were epigenetically poised to promote cancer development driven by IL-4/IL-33/IgG responses. Notably, pre-exposure to ERHs accelerated carcinogen-induced LC in mice irrespective of sex. These findings suggest sex-based pMac response is involved in LC susceptibility, differences in cancer behavior and outcomes in women with LCINS. Funding Sources Pennsylvania Department of Heath (PI Soloff) Veteran’s Health Administration (I01 CX002558)(PI Soloff) Department of Cardiothoracic Surgery, University of Pittsburgh (PI Soloff) Topic Categories Immune Mechanisms of Human Disease (HUM)

Cytochrome P450 (CYP) enzymes are involved in the metabolism of xenobiotic and carcinogen. In the study, we evaluated the association of CYP2J2 and CYP2C9 variants with lung cancer. Five polymorphisms in CYP2J2 and four polymorphisms in CYP2C9 were genotyped in 507 lung cancer patients and 505 controls with Agena MassARRAY platform. The linkage of variants with lung cancer risk was evaluated by odds ratio (OR) and 95% confidence interval (CI) in genetic models and haplotype analyses. We found that CYP2C9 rs1934967 alleles were associated with lung cancer risk (P < 0.05). In stratified analysis, rs2280274 (women, non-smoker, non-drinker and lymphatic metastasis), rs11207535 (non-smoker and non-drinker), rs10889159 (non-smoker and non-drinker) of CYP2J2, whereas rs1934967 (age ≤ 60, BMI > 24, squamous carcinoma) of CYP2C9 decreased lung cancer risk (P < 0.05). In addition, the results of linkage disequilibrium (LD) analysis showed that rs2280274|rs4388726 - TG (with adjustment: P = 0.042) of CYP2J2 and rs10509679|rs1934967| rs1934968|rs9332220 - GTGG (without adjustment: P = 0.044) of CYP2C9 were linked with a significantly decreased lung cancer risk. Our results indicated genetic variants in CYP2J2 and CYP2C9 might contribute to the susceptibility of lung cancer in Chinese population.

Abstract Description In recent decades, the incidence of lung cancer (LC) in never smokers (LCINS) has steadily increased, now the 5th leading cause of cancer mortality, and environmental respiratory hazards (ERHs) are implicated in LCINS etiology. Macrophages (Mφ) pre-condition the lung to support tumor initiation, but how the Mφ response to ERHs effects the pre-malignant microenvironment is unknown. We performed spatial transcriptomics on tumor samples from 156 LC patients, ∼20% never smokers, and 70 paired non-malignant lung tissues. Transcriptional profiles were generated from Mφs and local epithelium enriched or devoid of Mφ infiltrate. Compared to smokers, Mφs in LCINS tumors expressed distinct profiles associated with antigen uptake, degranulation, and IFN signaling. Cancer cells adjacent to Mφ in LCINS tumors upregulated IL-10, TLR, growth factor signaling and tissue remodeling pathways which were absent in Mφ devoid regions. Geospatial modeling of patient ERH exposures correlated with increased LCINS Mφ gene signatures in both tumors and non-malignant lung tissues. Lung Mφs from ERH exposed mice confirmed LCINS expression profiles associated with cancer development and were epigenetically sustained via H3K4me1 and chromatin remodeling and transient ERH exposure established wound-healing Mφs which increased LC burden upon carcinogen challenge. These findings indicate that epigenetic adaptation of Mφs in response to ERHs may contribute to increased LC susceptibility in never smokers. Funding Sources VA Merit Award 01CX00255; Pennsylvania Department of Health; University of Pittsburgh Department of Cardiothoracic Surgery Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Introduction: Lung cancer is one of the most prevalent cancers, with high mortality rate. Chemotherapy is a fundamental component of the treatment. However, the response varies among individuals. Objective: This study investigated the association of the POLR2E rs3787016 polymorphism with lung cancer susceptibility and platinum-based chemotherapy response. Methods: The study included 498 pulmonary carcinoma patients and 213 healthy individuals. Of these, 467 cases received at least two cycles of platinum-based chemotherapy The POLR2E rs3787016 genotyping was performed using time-of-flight mass spectrometry. Unconditional logistic regression analyses were used to evaluate the association of the genotype with pulmonary carcinoma susceptibility, as well as platinum-based chemotherapy response. Results: The study found no statistically significant association between POLR2E rs3787016 and susceptibility to pulmonary carcinoma (additive model: adjusted OR [aOR] = 1.012, 95% confidence interval [CI] = 0.781&amp;ndash;1.310, p=0.930; dominant model: aOR = 0.794, 95% CI = 0.518&amp;ndash;1.217, p=0.289; recessive model: aOR = 1.303, 95% CI = 0.847&amp;ndash;2.003, p=0.228). Logistic regression analysis demonstrated no meaningful association between POLR2E rs3787016 and the efficacy of platinum-based chemotherapy (additive model: aOR = 0.901, 95% CI = 0.688&amp;ndash;1.181, p=0.450; dominant model: aOR = 0.900, 95% CI = 0.578&amp;ndash;1.401, p=0.642; recessive model: aOR = 0.840, 95% CI = 0.541&amp;ndash;1.306, p=0.439). Besides, no substantial association was found between POLR2E rs3787016 polymorphism and the 5-year overall survival. Conclusion: Current evidence does not support POLR2E rs3787016 as a potential biomarker for predicting susceptibility to pulmonary carcinoma and the therapeutic efficacy of platinum-based chemotherapy in Chinese patients.

ABSTRACTBackgroundGenome‐wide association studies (GWAS) have identified over 80 susceptibility loci for lung cancer risk. However, the genes underlying these associations remain largely unknown.MethodsWe 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.ResultsA 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.ConclusionOur TWAS identified over 50 candidate susceptibility genes for lung cancer, providing new insights into lung cancer genetics.

Lung cancer (LC) is the leading cause of cancer-related deaths globally. Genetic variants in mismatch repair (MMR) genes, such as MutS homolog 2 (MSH2), MutS homolog 6 (MSH6) and MutL homolog 1 (MLH1), may influence individual susceptibility and clinical outcomes in LC. This study investigated the associations of genetic polymorphisms in MSH2, MSH6, and MLH1 with susceptibility and survival outcomes in lung cancer patients in the Guangxi Zhuang population. This study included a cohort of 192 LC patients and 262 healthy controls. The association of MSH2, MSH6, and MLH1 polymorphisms with susceptibility to small cell lung cancer (SCLC), lung adenocarcinoma (LUAD), and lung squamous carcinoma (LUSC) was evaluated using case-control methods, and protein expression differences were analysed by immunohistochemistry. The genotypes of genetic variations were detected using high-throughput SNP-scan technology. The Kaplan-Meier survival curve and log-rank test were used to assess the influence of individual genetic variants on prognostic outcomes in lung cancer patients. Multivariate logistic regression identified significant associations of rs2303428 and rs1042821 with increased lung cancer risk, especially in SCLC and LUSC. The GA and GG genotypes of rs1042821 were linked to higher SCLC risk (OR = 4.415 and 2.685; P = 0.019), the TC genotype of rs2303428 was associated with elevated LUSC risk (OR = 3.993; P = 0.034). No associations were found for rs1800734 or in LUAD. Immunohistochemistry showed increased MSH2 and MSH6 expression in risk genotypes, with no genotype-related changes in MLH1. In LUAD, the CC genotype of rs2300789 was associated with poorer overall survival compared to TC (P = 0.047), with no significant differences in other comparisons. rs2303428 and rs1042821 polymorphisms were associated with increased lung cancer susceptibility and altered protein expression. Additionally, the CC genotype of rs2300789 was linked to poorer overall survival in LUAD.

Genetic analysis in African ancestry populations reveals genetic contributors to lung cancer susceptibility.

Genome wide association studies (GWASs) have revealed several lung cancer susceptibility loci; however, we still face key issues such as how to identify more 'high-frequency and inefficient' variants and decipher the causal variants. Alternative polyadenylation (APA) can shorten or prolong the 3'UTR of mRNA containing cis regulatory elements, which plays an important role in post transcriptional regulation. Specific variants can affect the 3'UTR APA, leading to differences in the risk of lung cancer among individuals carrying different alleles. In this study, a cross-ancestry two-stage case-control design was used to evaluate the associations of 3'UTR APA related variants (3'aQTL SNPs, 3'aSNPs) defined by GTEx in normal lung tissues with the risk of lung cancer based on the genome-wide meta-analysis (GWMA) from FinnGen, UK Biobank and VA Million Veteran Program (MVP), including 28,557 cases and 1,355,961 controls. The promising variants were validated in an independent Chinese population with 1169 lung cancer cases and 1046 controls. Functional annotations of the identified 3'aSNP and related genes were performed based on multiple public databases. Finally, we identified a potential 3'aSNP rs11583258 associated with the risk of lung cancer both in the GWMA [OR = 1.04 (1.02-1.06), P = 1.00 × 10-4] and in the validation stage [OR = 1.08 (1.01-1.16), P = 1.01 × 10-2] at 1p36.11. Function annotation integrating the results of multiple public datasets suggested the variants in this region might affect both the length of the 3'UTR of the UBXN11 transcripts and the expression of UBXN11 to affect the susceptibility of lung cancer.