Supplementary Figure S17 shows Kaplan-Meier (KM) survival curves for relapse-free survival stratified by NS-LUAD expression subtypes in (A) patients with stage IA tumors, (B) patients with stage I tumors harboring no EGFR mutations or ALK fusions, or with no clinical records indicating treatment with tyrosine kinase inhibitor (non-TKI subset). P-values and hazard ratios (HR) were calculated using Cox proportional hazards models adjusted for age and sex. The number of samples in each subgroup is indicated on the KM curves. Unless otherwise specified, p-values are based on 10-year overall survival; for comparisons involving the chaotic subtype, 5-year overall survival rates were used owing to its association with advanced tumor stage. For the non-TKI subset, comparisons between the chaotic and steady subtypes were based on 10-year overall survival due to the absence of death events within the 5-year time window.

Despite promising results in using deep learning to infer genetic features from histological whole-slide images (WSIs), no prior studies have specifically applied these methods to lung adenocarcinomas from subjects who have never smoked tobacco (NS-LUAD) – a molecularly and histologically distinct subset of lung cancer. Existing models have focused on LUAD from predominantly smoker populations, with limited molecular scope and variable performance. Here, we propose a customized deep convolutional neural network based on ResNet50 architecture, optimized for multilabel classification for NS-LUAD, enabling simultaneous prediction of 16 molecular alterations from a single H&E-stained WSI. Key architectural modifications included a simplified two-layer residual block without bottleneck layers, selective shortcut connections, and a sigmoid-based classification head for independent prediction of each alteration, designed to reduce computational complexity while maintaining predictive accuracy. The model was trained and evaluated on 495 WSIs from the Sherlock-Lung study (70% training with 10% internal test set for 10-fold cross-validation, and 30% held-out validation set for final evaluation). For the held-out validation data, our model achieved high areas under the receiver operating characteristic curve [AUROC] values =0.84-0.93 for detecting 11 features: EGFR, KRAS, TP53, RBM10 mutations, MDM2 amplification, kataegis, CDKN2A deletion, ALK fusion, whole-genome doubling, and EGFR hotspot mutations (p.L858R and p.E746_A750del). Performance was low to moderate for tumor mutational burden (AUROC=0.67), APOBEC mutational signature (AUROC=0.57), and KRAS hotspot mutations (p.G12C: AUROC=0.74, p.G12V: AUROC=0.55, p.G12D: AUROC=0.43). Compared to results from established architectures such as Inception-v3 on the same WSIs, our model demonstrated significantly improved performance for most features. With further optimization, our model could support triaging for molecular testing and inform precision treatment strategies for NS-LUAD patients.

Lung cancer incidence among never-smoking women in Xuanwei, China, is among the highest worldwide and is primarily attributed to household air pollution (HAP) from smoky (bituminous) coal combustion, with early-life exposure identified as playing a critical role. We conducted epigenome-wide DNA methylation (DNAm) analyses of HAP exposure and its polycyclic aromatic hydrocarbon (PAH) constituents across exposure windows. Leukocyte DNAm was measured in 106 never-smoking women, including 23 individuals with repeated measurements. Cooking fuel use and stove type was obtained through questionnaire, and comprehensive personal and environmental air monitoring was conducted. Validated exposure models estimated 43 HAP constituents, predominantly PAHs, across childhood, current, and cumulative exposure windows, and PAH clusters were derived via hierarchical clustering. Generalized estimating equations were used to identify CpG sites associated with HAP exposure and PAH clusters, including 5-methylchrysene, a methylated PAH previously linked to lung cancer. We identified several differentially methylated CpG sites, predominantly hypomethylated with higher HAP exposure. Although some DNAm signatures overlapped with those observed in smoking, the majority were distinct. Notably, higher current exposure to 5-methylchrysene was significantly associated with hypomethylation at cg05575921 (AHRR; p = 2.05x10-06), an established smoking marker. Life-course analyses indicated lasting DNAm variations with both childhood and cumulative PAH exposures at loci such as SLC43A2. Within the PAH clusters, 5-methylchrysene was a key contributor to DNAm variations. Top CpG sites were linked to immune regulation, G-protein coupled signaling, and molecular mechanisms of cancer and other disease pathways. These findings provide novel insight into HAP-induced DNAm changes and their potential health implications.

10561 Background: Individuals without prior tobacco use account for a growing proportion of lung cancer cases, but the impact of prior lung diseases on lung cancer risk in this population remains unclear. We performed a meta-analysis of studies examining the association of prior lung diseases – tuberculosis (TB), asthma (AS), and chronic bronchitis (CB) – with lung cancer risk among individuals without prior tobacco use. Methods: PubMed and Embase were searched from inception to Jan 20 th , 2024 for studies examining the association between TB, AS, and/or CB and lung cancer risk in populations over 18 years old who never smoke. Studies were excluded if (1) “never-smoking” was not defined as having never smoked or smoked less than 100 cigarettes in their lifetime; (2) they were not written in English, Mandarin, or Korean; (2) odds ratios (OR)/hazard ratios (HR) were not reported. Summary effect estimates with 95% CI were calculated for case-control (summary OR) and cohort (summary HR) studies using random effects models with inverse variance weighting. Subgroup meta-analyses and meta-regressions were conducted among case-control studies by continent [Asia vs. non-Asia (North America and Europe)]. There was insufficient information to examine differences across the subgroups of sex and race and ethnicity. Results: 17 case-control studies and five cohort studies were examined. Among case-control studies, history of TB (13 studies), AS (10 studies), and CB (nine studies) were statistically significantly associated with an increased risk of lung cancer in patients without prior tobacco use (TB: summary OR=1.75, 95% CI 1.43-2.15, I 2 = 29; AS: summary OR=1.46, 95% CI 1.06-2.02, I 2 = 34; CB: summary OR=1.36, 95% CI 1.07-1.72, I 2 = 0). Among cohort studies, TB (four studies) was associated with a statistically significant increase in lung cancer risk (summary HR=1.81, 95% CI 1.34-2.44, I 2 = 44). There were insufficient number of cohort studies to summarize the associations of CB (no studies) or AS (one study) with lung cancer risk. The summary OR for TB and AS with lung cancer risk was larger in Asian vs. non-Asian populations (TB: Asian populations summary OR=1.79 95% CI 1.40-2.28, I 2 = 47 vs. non-Asian populations summary OR=1.47 95% CI 0.88-2.44, I 2 = 0; AS: Asian populations summary OR=2.63 95% CI 1.10-6.28, I 2 = 40 vs. non-Asian populations summary OR=1.31 95% CI 0.96-1.79, I 2 = 20). However, there was no evidence of heterogeneity in summary OR by continent using meta-regression (TB: p=0.58; AS: p=0.16). Conclusions: In this meta-analysis, history of TB, AS, and CB were associated with lung cancer risk among populations who never smoked, informing potential etiologies of the shifting global burden of lung cancer. Future studies examining these associations should analyze more diverse patient populations and disaggregate findings by sex, race and ethnicity, socioeconomic status, and geography.

Supplementary Figure S16 shows proportions of (A) interchromosome and intrachromosome fusions and (B) fusions supported by structural variants (SV) across NS-LUAD expression subtypes. (C) Summary of types of genes involved in fusions. Circle sizes indicate the numbers of genes. D-E, (D) Numbers of protein-coding gene fusions per sample and (E) numbers of in-frame gene fusions per sample across NS-LUAD expression subtypes. Mean values are indicated by the yellow lines. P-values from two-sided Mann-Whitney U-test are shown.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, but its genetic architecture has not been fully characterized, particularly in Asian populations. Here, we perform a multi-ancestry meta-analysis of 33,712 RCC cases and 845,786 controls, including individuals of East Asian (5,313 cases and 96,912 controls), European (25,890 cases and 743,585 controls), African American (897 cases and 3,109 controls), and Latin American ancestry (1,612 cases and 2,180 controls), which unveils 10 novel RCC-associated loci and a Chinese-specific locus at 12p13.33. Leveraging genome-wide association study (GWAS) data and cross-ancestry expression quantitative trait loci (eQTLs) mapping from 266 kidney tissues, we refine the identification of putative causal variants and genes implicated in RCC. These findings are substantiated through CRISPR-based screenings and multiplexed single-cell perturbations. Additionally, we functionally validate a novel association between rs28684409 and the oncogene RPL4 at the complex genetic locus 15q22.31. This comprehensive genetic investigation underscores the utility of integrating cross-ancestry GWASs, QTLs, and functional screens to elucidate the genetic underpinnings of complex diseases.

Supplementary Table S5 shows gene signatures of hallmark genes and lung developmental pathways.

Excess lung cancer risk in Xuanwei and Fuyuan, China, has been attributed to household air pollution from use of a locally sourced smoky (bituminous) coal. However, the carcinogenic mechanisms remain unclear. Given the important role of inflammation in lung cancer development, this study compared the proinflammatory potentials of the particulate phase of smoky coal emissions with those of a locally sourced smokeless (anthracite) coal, which poses a lower lung cancer risk. A co-culture model of lung epithelial (Calu-3) and macrophage (differentiated THP-1) cells was exposed to aerosolized particulates, followed by analysis at 24 h exposure (R0) and after 24 h of recovery (R24). Cytotoxicity was minimal, with lactate dehydrogenase (LDH) release consistently under 15% of the total LDH content. Particulate exposure reduced transepithelial electric resistance (TEER) at R0, with partial recovery by R24, indicating sustained epithelial barrier damage. IL-6 release occurred at R0 in a dose-dependent manner but normalized by R24 for most samples. No significant IL-8 release was observed. The inflammatory and toxic potential (TEER reduction and IL-6/IL-8 changes) were similar across coal types and ventilation conditions. The observed potencies showed no correlation with polycyclic aromatic hydrocarbons (PAHs) content and the observed lung cancer risks of the coal samples. In summary, transient inflammation and lasting barrier damage were observed with little contrast between different coal samples. As these results do not explain the variation of lung cancer risks, further studies examining alternative cellular pathways and biological effects are needed to elucidate the mechanisms driving lung cancer in this population.

Evidence for an association between insulin-like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF-I concentrations and risk of MM by combining baseline serological data among UK Biobank participants (n = 444 187; 732 incident MM) with a two-sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF-I and IGF-binding protein 3 (IGFBP-3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF-I level was positively associated with MM risk Hazard ratio-HR-per one standard deviation-SD-increase (HR1-SD = 1.11, 95% confidence interval [CI]: 1.01-1.22; p-value = 0.03), especially closer to diagnosis. Genetically inferred IGF-I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05-1.54) but not with any other LNs. Genetically inferred IGFBP-3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF-I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR1-SD in obese male = 1.36, 95% CI: 1.14-1.61). Our serological and MR analyses suggest a contributing role of IGF-I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex-specific adiposity.

BACKGROUND:Experimental models indicate that oxidative stress may shift from promoting to suppressing tumor development as cancer progresses. METHODS:We conducted a nested case-control study within 2 Shanghai cohorts for primary analysis and 1 US cohort for replication. Over a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident colorectal cancer (CRC) cases were identified and matched to 1 control each. In the US cohort, 251 incident CRC cases were matched to 2 controls each. Systemic oxidative stress was assessed using urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) via ultra-performance liquid chromatography tandem mass spectrometry. Multivariable-adjusted odds ratios for CRC risk were calculated. RESULTS:After adjusting for selected covariates, an inversion association between oxidative stress markers and CRC risk was observed in the Shanghai cohorts and independently replicated in the US cohort. This inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years following enrollment. Odds ratios for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (95% confidence interval [CI] = 1.39 to 2.53) and 0.48 (95% CI = 0.37 to 0.63), respectively, demonstrating a threefold difference in risk, with a P value for overall association less than .001. A similar pattern was observed for 8-oxo-Guo. No statistically significant associations were found for CRC diagnosed beyond 5 years of enrollment. CONCLUSION:This novel finding of a time-dependent inverse relationship between systemic oxidative stress and CRC risk, if further confirmed, may prompt a reevaluation of redox-based chemoprevention strategies.

Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. "Steady," marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. "Proliferative" shows high proliferation markers, TP53 mutations, and gene fusions. "Chaotic," with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. SIGNIFICANCE:The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423.

Abstract Background: Wildfires are becoming more frequent and severe, reversing decades of progress in reducing fine particulate matter (PM2.5) in the United States. Although wildfire smoke (WFS) contains numerous carcinogens and toxicants, its association with cancer incidence remains unclear. Methods: We examined associations between WFS exposure and cancer incidence in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The PLCO trial prospectively assessed cancer incidence from enrollment (1993-2001) through 2018. WFS exposure was quantified monthly at participants’ residences using near-ground WFS PM2.5, WFS black carbon (BC), and satellite-derived WFS plume-day counts from 2006 until first cancer diagnosis or last contact. Guided by evidence that three years of air-pollution exposure can influence the development of EGFR-positive lung adenocarcinoma, WFS exposure was modeled as a time-varying variable using 36-month moving averages preceding each month. Hazard ratios (HRs) were estimated using Cox proportional hazards models stratified by study center, with proportional hazards assumptions verified. Restricted cubic splines were applied to evaluate dose-response relationships. Covariates included age, sex, race and ethnicity, education, smoking history, body mass index, and trial arm. Results: Among 91,460 PLCO participants with linked WFS exposure data, we identified incident cases of 1,758 lung, 800 colorectal, 1,739 breast, 242 ovarian, 896 bladder, and 1,696 hematopoietic cancers, and 1,127 melanoma during 2006-2018. Median (range) 36-month moving-averages were 0.37 (0.0083-1.72) µg/m3 for WFS PM2.5, 0.0083 (0.00-0.21) µg/m3 for WFS BC, and 1.94 (0.097-7.18) days for monthly WFS plume-day counts. Restricted cubic splines indicated statistically significant associations (P<0.05) of WFS exposure with increased risks of lung, colorectal, breast, bladder, and hematopoietic cancers, with an approximate linear dose-response observed for most analyses. Moreover, each 1 µg/m3 increase in the 36-month moving-average of WFS PM2.5 was associated with higher risks of lung (HR=1.92; 95% CI: 1.18, 3.15), colorectal (2.31; 1.11, 4.81), breast (2.09; 1.34, 3.26), bladder (3.49; 1.66, 7.34), and hematopoietic (1.63; 1.02, 2.60) cancers. No associations were found for ovarian cancer or melanoma. Results for WFS plume-day counts were generally consistent with those for WFS PM2.5, whereas associations for WFS BC exposure were observed only for breast and bladder cancers. Conclusion: WFS exposure was associated with the risk of lung, colorectal, breast, bladder, and hematopoietic cancers. Findings need to be replicated in additional cohorts. Citation Format: Qizhen Wu, Lisa Sinclair, Vernon S. Pankratz, Qing Lan, Nathaniel Rothman, Rena Jones, Su Zhang, Shuguang Leng. Wildfire smoke and cancer risk in the United States: Evidence from the PLCO Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6252.

Background:While smoking is inversely associated with Parkinson's disease (PD) risk, its relationship with amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA) remains unclear, particularly in Asian populations. We investigated these associations in a Chinese case-control study. Methods:We recruited newly diagnosed ALS (n=430), MSA (n=271), PD (n=523) cases and hospital-based controls (n=1033) in Sichuan, China. Logistic regression models were used to evaluate associations between smoking and disease risks, adjusting for demographic, lifestyle and occupational factors. Results:Compared with never-smokers, the adjusted ORs and 95% CIs of ALS for current and former smokers were 1.00 (0.61 to 1.65) and 1.79 (1.01 to 3.17), respectively. For MSA, ORs were 1.27 (0.73 to 2.23) for current smokers and 2.54 (1.41 to 4.60) for former smokers. Individuals who quit within 4 years before diagnosis showed the highest risk of ALS (OR=1.93, 95% CI 0.96 to 3.88) and MSA (OR=2.09, 95% CI 1.11 to 3.93). For both ALS and MSA, no consistent trend was found with increasing smoking duration or pack-years. In contrast, ever-smokers had a significantly lower PD risk (OR=0.49, 95% CI 0.33 to 0.71), particularly current smokers (OR=0.30, 95% CI 0.19 to 0.48). Longer smoking duration and higher cumulative smoking were also linked to PD risk with clear negative exposure-response patterns (P trend=0.039 and 0.029, respectively). Conclusions:Consistent with findings in non-Asian populations, smoking was inversely associated with PD risks in the Chinese population. For ALS and MSA, we found evidence suggestive of positive relationships with cigarette smoking, but no clear exposure-response relationships were observed.

BACKGROUND:Lung adenocarcinoma (LUAD) is the most common type of lung cancer. A recent genome-wide association study of lung adenocarcinoma in East Asia reported 28 independent susceptibility variants across 25 loci and identified 2 genes whose genetically predicted expression levels are associated with lung adenocarcinoma risk, using an ancestry-matched lung tissue expression quantitative trait loci (QTL) dataset. It is desirable to identify additional susceptibility loci and to understand their underlying biological mechanisms. METHODS:Using an expanded genome-wide association study of lung adenocarcinoma in East Asia and ancestry-matched lung tissue expression QTL and DNA methylation QTL datasets, we performed transcriptome-wide association studies and DNA methylome-wide association studies simultaneously and examined the association between measured expression of genes and DNA methylation of nearby CpGs. Genes and nearby CpGs are termed CpG-gene-LUAD trios if these 3 associations hold simultaneously. RESULTS:At a Bonferroni-corrected P value less than .05, we identified a new susceptibility locus (6p21.31; lead single-nucleotide polymorphism rs7772643), 10 lung adenocarcinoma-associated genes, and 86 lung adenocarcinoma-associated CpGs. At a false discovery rate q value less than 0.05, we identified 28 lung adenocarcinoma-associated genes, 220 lung adenocarcinoma-associated CpGs, and 45 CpG-gene-LUAD trios; among them, 43 were direction-matched regarding these 3 associations. These show that 23 of the known 28 susceptibility variants for lung adenocarcinoma in East Asia are near these genes or CpGs and MARCH3, ELF5, IKZF3, GSDMB, CCDC116, and DSP are putative novel candidate genes. Few of them were reported in lung adenocarcinoma in European populations. CONCLUSIONS:This study substantially advances our understanding of the etiology of lung adenocarcinoma in East Asia and could be useful in developing translational applications.

BackgroundVenous thromboembolism (VTE) represents a major and potentially fatal complication among patients with intracerebral hemorrhage (ICH); however, accurate risk stratification remains difficult in this population. The present study sought to determine independent predictors of VTE in patients with ICH using data derived from a large multicenter critical care database.MethodsA retrospective cohort study was performed using the eICU Collaborative Research Database. Adult patients with a diagnosis of ICH were included. VTE events were identified through an integrated multi-modal approach incorporating diagnostic coding, clinical text mining, and records of therapeutic anticoagulation. Data on baseline demographics, comorbid conditions, laboratory parameters, and thromboprophylaxis practices were collected. Univariate and multivariate logistic regression models were applied to identify independent risk factors for VTE. Sensitivity analyses were conducted using alternative VTE definitions to assess the robustness of the findings. Interaction analyses and additional sensitivity analyses excluding anticoagulation-only VTE cases were performed to further evaluate the robustness of the primary findings.ResultsA total of 785 patients with ICH were analyzed, of whom 53 (6.75%) developed VTE during hospitalization. In univariate analyses, nine variables were significantly associated with VTE occurrence, including atrial fibrillation (AF) (OR = 5.75, 95% CI: 2.95–11.21, p < 0.001), chronic obstructive pulmonary disease (COPD) (OR = 6.81, 95% CI: 2.67–17.38, p < 0.001), and use of mechanical ventilation (OR = 2.53, 95% CI: 1.38–4.64, p = 0.003). After adjustment for potential confounders in multivariate analysis, atrial fibrillation emerged as the only independent risk factor for VTE (adjusted OR = 3.84, 95% CI: 1.75–8.41, p < 0.001). The incidence of VTE was substantially higher among patients with AF compared with those without AF, representing an unadjusted 4.6-fold higher VTE incidence (24.2% vs. 5.3%). This association remained consistent across multiple sensitivity analyses, including analyses excluding anticoagulation-only VTE cases (adjusted OR = 3.99, 95% CI: 1.02–15.55, p = 0.046).ConclusionAtrial fibrillation was the only independent risk factor for VTE after multivariable adjustment, conferring an approximately four-fold increase in VTE risk, and should be interpreted as a clinical risk marker rather than a direct causal factor. Patients with ICH complicated by AF constitute a particularly high-risk subgroup and may benefit from intensified surveillance and individualized thromboprophylaxis strategies.

Supplementary Table S10 shows NS-LUAD expression subtypes predicted by the 60-gene signature in the GIS cohort.

Supplementary Figure S3 shows consensus matrix for NMF rank 2 to 10.

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma with poor prognosis, even with treatment. Despite its clinical importance, the etiology of MCL remains largely unknown. Some studies have reported a positive association with family history, suggesting that genetic factors could contribute to risk. Methods: To identify germline genetic variants associated with risk, we conducted the first genome-wide association studies (GWAS) and GWAS meta-analysis for MCL, comprising 1,163 cases and 61,271 controls. The most significant loci were taken forward for replication in three independent studies, including 576 cases and 771,773 controls. To identify potential target genes and pathways of discovered loci, we conducted F-MAGMA, colocalization, and transcriptome-wide association study (TWAS) analyses. To gain insight into underlying regulatory mechanisms, we performed integrative epigenomic analyses using DNase I hotspots and histone mark ChIP-seq data across diverse cell types applying the FORGE2 framework. Results: In the joint analyses, we identified eight genome-wide significant loci (P<5x10-8) associated with MCL risk, several of which were located near genes with known DNA repair (ATM), telomere (TERT), or RNA-binding functions (RBM20). Further analyses using F-MAGMA, which uses DNase-seq data to prioritize genes from GWAS, identified genes that were significantly associated with risk, including SP140, a chromatin reader and immune regulator of pathogen response. This gene also displayed strong colocalization with our lead variant in whole blood (COLOC posterior probability PP4=0.97). TWAS demonstrated significant associations with SP140 and ACTA2, which has been linked to cell proliferation (P<3x10-6). Enrichment for DNase I hotspots was observed in B and T lymphocytes (q-value<0.05), providing evidence for a role in immune cell-specific regulatory regions. Enrichment for enhancer-associated histone mark H3K4me1 was observed in B cells (q-value<0.01), highlighting a role for immune cell-specific enhancers. Transcription factor (TF) motif enrichment analysis pointed to TFs critical for B-cell development and differentiation, notably TCF3 and EP300 (q<0.01 for both), suggesting an association between B-cell lineage regulation and MCL risk. Finally, genome-wide SNP-based heritability was estimated to be 17%, underscoring the importance of common variants in MCL risk. Conclusion: Our study provides novel insight into the inherited susceptibility of MCL by identifying eight significant loci and estimating substantial common variant heritability. These findings highlight a role for several distinct biological pathways -specifically DNA repair, telomerase function, and B-cell differentiation- in the etiology of MCL, offering new targets for mechanistic investigation. Citation Format: Charles E. Breeze, Alyssa Clay-Gilmour, Hanla A. Park, Ólafur B. Davíðsson, Angelica Macauda, Brenda M. Birmann, Elizabeth E. Brown, Murat Güler, Michelle A. T. Hildebrandt, Alexandra Nieters, Krystle Ong, Jojo Biel-Nielsen Dietz, Karin E. Smedby, Karl Smith-Byrne, Rosalie Griffin, Sophia S. Wang, Susan Slager, James R. Cerhan, Jonathan N. Hofmann, Qing Lan, Nathaniel Rothman, Ingrid Glimelius, Henrik Hjalgrim, James Mckay, Sonja I. Berndt. Genome-wide association study of mantle cell lymphoma identifies novel loci suggesting a critical role for B-cell chromatin readers and DNA repair mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3602.

Supplementary Table S8 shows centroids of the 60-gene signature for the classification of NS-LUAD expression subtype.