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Background: Rare, functionally deleterious genetic variants have been implicated as having substantially larger effect sizes than common variants, potentially accounting for much of the missing heritability in lung cancer (LC). Over 25 years, the Genetic Epidemiology of LC Consortium (GELCC) has curated an invaluable resource of specimens and data from individuals with a strong family history of LC. Methods: Whole-genome and exome sequencing data were analyzed in 129 high-risk familial LC (FLC) families, defined as having two first-degree relatives or three or more second-degree relatives affected by LC (177 affected FLC and 309 unaffected relatives). The discovery focused on rare (allele frequency < 1% in gnomAD global population) and deleterious variations (missense, stop-gained, frameshift) enriched in FLC. Promising candidates were further external validated in 2,408 sporadic lung cancer (SLC) cases and 885 population controls from the International Lung Cancer Consortium. Results: We identified 168 variants with moderate-to-large effects on FLC risk, 100 of which were validated for SLC risk (Table 1 Table 1. Top 20 candidates Gene Rare (MAF < 1%), deleterious variants No. of variant carrier counts Odds Ratio, LC vs Control FLC | Relative | SLC | Control FLC+SLC SLC Oncogene ERBB3 / HER3 p.A1131T 3 | 1 | 2 | 0 35 15 JAK p.V651M 2 | 3 | 7 | 0 62 51 NOTCH3 p.R1560P 3 | 1 | 4 | 0 48 29 ROS1 p.N785X 6 | 4 | 10 | 0 110 74 USP6 p.R522 fs del 3 | 6 | 6 | 0 62 45 Tumor suppressor gene ATM p.L2332P 3 | 2 | 8 | 0 76 59 LZTS2 p.K458R 4 | 4 | 18 | 0 152 133 NPIPB13 p.V270 fs del 13 | 14 | 10 | 0 159 74 PARK2 / PRKN p.P153R 3 | 3 | 8 | 0 76 59 RB1 p.A525G 3 | 0 | 6 | 0 62 45 SLX4 p.S1716T 3 | 2 | 9 | 0 83 66 SYNE1 p.M6566I 2 | 0 | 7 | 0 62 52 TGFBRAP1 p.T301R 5 | 0 | 11 | 0 110 82 WNK1 p.K583 fs del 4 | 0 | 23 | 0 187 171 Other cancer-associated gene CFTR p.R74W 4 | 2 | 4 | 0 55 30 FLG p.R3404 fs del 7 | 2 | 4 | 0 69 30 LTN1 p.R349H 6 | 1 | 10 | 0 110 74 MLNR p.Q334 fs del 3 | 2 | 19 | 0 152 134 SLC39A11 p.R38Q 4 | 2 | 13 | 0 117 96 TTYH2 p.R493C 5 | 4 | 14 | 0 131 104 Dose effect of the top candidates No. candidates 0 variant allele 67 | 194 | 1911 | 834 reference reference 1 variant allele 50 | 66 | 363 | 50 3.5 (2.6 - 4.7) 3.2 (2.3 - 4.3) 2 variant alleles 15 | 18 | 62 | 1 32 (4.5 - 230) 27 (3.8 - 195) 3+ variant alleles 45 | 31 | 72 | 0 98 (6 - 1506) 62 (3.9 -1012) lists 20 top hits). Among these, 15 variants mapped to our previously identified lung cancer linkage locus at 6q23-25 (ROS1, PARK2, SYNE1). Others were enriched in oncogenes (ERBB3, JAK1, MET), tumor suppressor genes (ATM, BRCA2, RB1), and genes involved in the extracellular matrix (COL6A3, FLG, MUC5B). Importantly, individuals carrying more than two combinations of these variants exhibited exceptionally strong dose effects, with odds ratios (OR) exceeding 27. Conclusion: Our findings underscore the significant role of rare, high-penetrance variants in FLC etiology and highlight promising targets for early detection and personalized treatment. Future in-depth mechanistic studies are planned to evaluate the pathogenic effects of these specific alleles. Citation Format: Yanhong Liu, Claudio Pikielny, Xiangjun Xiao, Bo Peng, Yafang Li, Jinyoung Byun, Chao Cheng, Dakai Zhu, Spiridon Tsavachidis, Colette Gaba, Elena Kupert, Ellen L. Goode, Erin L. Crawford, Kristen Purrington, Marshall Anderson, Michael Cole, Paul Brennan, Geoffrey Liu, James McKay, John K. Field, Rayjean J. Hung, David C. Christiani, Diptasri Mandal, James C. Willey, Ann Schwartz, Joan Bailey-Wilson, Susan M. Pinney, Christopher I. Amos. High-penetrance rare variants underlying familial lung cancer risk: Insights from the Genetic Epidemiology of Lung Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3815.

Introduction: WM is a rare subtype of lymphoma, identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the somatic mutation, MYD88 L265P, which is observed in over 90% of WM patients. We previously identified two rare variants at 6p25.3 (EXOC2) and 14q32.13 (TCL1) that were significantly associated with an increased risk of WM/LPL (PMID: 30305637). However, the genetic basis for WM/LPL predisposition remains largely unknown. We conducted the largest WM/LPL GWAS to discover further germline susceptibility loci for WM/LPL. Methods: Our meta-analysis discovery set included 1,707 cases and 58,328 controls of European ancestry from the InterLymph Consortium, genotyped on a high-density SNP array and imputed to TOPMed, providing over 10 million common variants for association testing. Germline genetic loci with suggestive significance (P<5x10-6) were selected for replication in four independent sets (570 cases and 771,770 controls; UK Biobank, Copenhagen Hospital Biobank, FinnGen, Mayo Clinic), giving us a total of 2,277 WM/LPL cases and 831,098 controls. Conditional and sensitivity analyses were performed considering family history and sex. A transcriptome-wide association study (TWAS) was performed using FUSION with expression quantitative trait loci (eQTL) data from GTEx and Young Finns Study in whole blood, lymphocytes, and other tissues. Functional annotations were done using FUMA, F-MAGMA, FORGE, and OpenTarget. Colocalization was measured using CoLoC with whole blood gene expression data. Results & Discussion: We identified 11 germline genetic loci associated with WM/LPL risk that replicated and reached genome-wide significance (P< 5x10-8), including the two known loci on 6p25.3 and 14q32.13 and nine novel loci in the following regions: 6p25.3 (n=2 independent loci), 2q37.1, 9p13.2, 6p21.32, 10q23.31, 16q21, 1p31.1, and 15q15.1. Four of the discovered variants showed strong associations with WM/LPL [odds ratios (ORs) >10]. Enrichment was observed for enhancer and promoter elements in B-cells (FDR q < 0.01), and gene-based and colocalization analyses identified several potential biological pathways. Colocalization analyses show the intronic PAX5 risk variant on 9p (OR=1.5, P= 2.3x10-25) associated with whole blood eQTL expression of PAX5, which plays an essential role in regulating lymphoid progenitors to the B-lymphocyte lineage, as well as RP11-297B17.3 (RNA gene, antisense to PAX5). In addition, GWAS have shown this variant is in linkage disequilibrium (LD) with GWAS loci for CD20 on IgD+ CD38- B cell that represents a specific immunophenotype that helps identify and characterize B cells involved with WM and other similar conditions. The 2q37.1 (SP140) locus (OR=1.6, P=1.2x10-33) contains variants linked to chronic lymphocytic leukemia (CLL) and autoimmune diseases, including multiple sclerosis and Crohn's disease. This locus is important in chromatin-mediated gene regulation, suggesting a significant role in the immune system. The specific variant influences exon-skipping and potentially protein expression, altering the gene's function. The variants on 10q23.31 in FAS (OR=1.3, P=4.4x10-13) and 15q15.1 (OR=1.2, P=8.5x10-11) in BCL2 modifying factor (BMF), are in strong LD with known CLL susceptibility variants. The 15q variant is also linked with multiple lymphoid leukemia GW significant SNPs. Sex-specific analyses identified one novel locus at 20q13.33 associated with the expression of ZGPAT and UCKL1 in males (OR=1.9, P=9.5x10-10). TWAS identified associations with CRHR1 and CDKN2A; overexpression of both are shown to be associated with an increased risk of WM/LPL. Expression of CDKN2A has been linked to childhood acute lymphoblastic leukemia, while CRHR1 has been associated with breast cancer risk. Conclusions: Our study, the largest GWAS of WM to date, has identified 11 susceptibility loci, including two previously known and nine novel regions. The findings underscore the genetic complexity of WM, with the PAX5 and SP140 loci implicated in both chromatin-mediated gene regulation and immune system functions. These insights not only enhance our understanding of WM predisposition but also pave the way for future research focused on functional understanding of these loci, potentially leading to new therapeutic strategies.

Introduction: Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin lymphoma. Family history is a risk factor. Genome-wide association studies (GWAS) have identified several germline variants, especially within the HLA region, to be associated with an increased risk of FL, but these variants only explain a fraction (16%) of heritability. Here, we present novel findings from GWAS of FL uncovering multiple germline genetic variants contributing to disease susceptibility. Methods: A GWAS was performed comprised of a discovery analysis in 6,508 FL cases and 64,183 controls of European ancestry followed by a replication of the most significant variants (P<5x10-7) in 2,745 FL cases and 782,226 controls from the biobanks of UK, Copenhagen Hospital, FinnGen and Mayo Clinic . At 9,253 FL cases and 846,409 FL free controls imputed genome-wide, this is the largest FL GWAS of European genetic ancestry to date. HLA alleles were imputed, and Class I and Class II signals were analysed at the amino acid level. A transcriptome wide association study (TWAS) was performed using FUSION investigate relationship to expression in GTEx and Young Finns Study in whole blood and cross-tissue . Functional annotations were done using FUMA, F-MAGMA, Open Targets and FORGE. Colocalization was conducted using CoLoC with whole blood gene expression data to understand causal variants. Mendelian randomization (MR) was performed on blood cell traits and leukocyte telomere lengths (LTL) to infer their relationships with FL genetic risk. Results: We replicated the previously published susceptibility loci within and outside the HLA region, finding two additional independent SNPs at two known loci (P < 5 x10-8) and discovered thirteen novel, genome-wide significant loci located at chromosome 2q13, 3p13, 3p24.1,3q13, 3q24.1, 4q31.21, 6p21, 6p22, 7q31, 10p14, 10q22, 10q23, 17q12, 19p13 and 20p11 with P < 5 x10-8. These SNPs were located near genes that show relevance for B-cell biology, such as BCL2L11, FOXP1, CD86, EOMES, IZKF3, PRF1, KLF2 NKX2-2 and HLA Class I and Class II genes. TWAS uncovered a role for H2AX, IGKV2-29, IMP, UBE4A and IKZF3 and provided directionality of effect for associated transcripts. Colocalization analysis corroborated a positive association with IKZF3 expression showing a robust correlation with FL risk variants (posterior probability PP4>0.7). In addition, several genome-wide significant variants in IKZF3 colocalize with eQTLs across tissues. IKZF3 (Aiolos) is part of the Ikaros family of transcription factors, critically important to the regulation of B-cell development and function. Therapeutic strategies leveraging Immunomodulatory imide drugs (IMiDs) to degrade IKZF3 have shown efficacy in multiple myeloma, and we speculate may also have potential benefits in FL by enhancing anti-tumor immunity and disrupting malignant B-cell function. Gene-set analysis showed blood and spleen to be the most relevant tissues for FL risk variants with lymphocyte activation and immune cell type differentiation genes demonstrating enrichment based on gene-ontology terms. Associated traits included allergies, respiratory diseases (e.g., asthma phenotypes), inflammatory bowel diseases, type 1 diabetes (T1D), lipid levels and commonly measured blood cell traits, with some SNPs showing evidence of colocalization with select blood traits. Interestingly, no causal association to blood traits was observed using MR; however, MR analyses did reveal a strong association with LTL. For the HLA loci, FL shows a diverse set of amino acid associations in HLA Class I and Class II genes that extends beyond what is known from autoimmune disease associations, such as rheumatoid arthritis or T1D. Our study also reveals interesting biological insights about FL susceptibility, such as a novel locus intragenic to FOXP1, an activated oncogene preferentially expressed in FL and DLBCL tumors, but rarely observed in Hodgkin's lymphoma. High levels of FOXP1 are known to result in poor survival in FL. Conclusion: This large GWAS of FL has identified multiple susceptibility variants, uncovering interesting gene candidates for further pathophysiological characterization of FL risk and B-cell development. It suggests new biological pathways and genes that could be potential leads for drug development and targeting treatment, in addition to identifying genetically high-risk populations for FL susceptibility.

Introduction: Over 80,000 new cases of Non-Hodgkin's Lymphoma (NHL) are diagnosed annually, but modifiable risk factors are largely unknown. Circadian disruption has been identified as a risk factor for several cancers, including breast and prostate cancer, and affects immune cells such as Natural Killer (NK) cells and T-helper cells. Disruptions in circadian rhythms can lead to aberrant immune cell trafficking and proliferation. Despite this biological connection, evidence linking circadian disruptions to NHL remains inconclusive. Only single Mendelian Randomization (MR) study (PMID: 32895918) has explored the causal relationship between sleep traits and overall NHL risk, without examining NHL subtypes. Studies have shown distinct risk factor profiles among NHL subtypes. Therefore, this study aims to investigate the causal relationship between sleep traits and NHL subtypes in European populations using MR. Methods: We conducted a two-sample MR analyses using genome-wide association studies (GWAS) summary data on sleep traits and NHL subtypes. The GWAS summary statistics on sleep traits were obtained from publicly available UKBiobank datasets. The sleep traits analyzed included chronotype (N=449,734), insomnia (N=237,627), sleep duration (N=446,118), daytime sleepiness (N=452,071), short sleep (N=411,934), and long sleep (N=339,926). Only independent, genome-wide significant SNPs (p < 5×10-8) were considered as valid instruments. The NHL subtype-specific summary statistics came from the InterLymph including follicular lymphoma (FL: N=6,508 cases / 64,183 controls), mantle cell lymphoma (MCL: N=1,169 cases / 61,603 controls), and Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: N=1,697 cases / 59,333 controls). Our primary analysis used the random-effects inverse-variance weighted (IVW) method. In addition, we employed MR-Egger to adjust for directional pleiotropy. Heterogeneity in the MR results was evaluated with Cochran's Q statistic. Results: The IVW method did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes (FL,MCL,WM/LPL), but did yield several intriguing associations. Chronotype (early rising) showed a tendency towards a marginally an increased NHL risk across subtypes [Odds ratio (OR) range: 1.07 - 2.56]. Conversely, a decreased risk was noted for long sleep (≥ 9 hours vs. 7-8 hours) [OR range: 0.19 - 0.62], insomnia [OR range: 0.72 - 0.88], and short sleep (excludes MCL) [OR range: 0.12 - 0.72]. Confidence limit for long sleep was wide due to small number of variants (N=8). The MR-Egger regression analysis did not provide evidence of significant directional horizontal pleiotropy. The F-statistics for all sleep traits were greater than 10 indicating absences of weak instrument bias. Conclusions: Our study found no statistically significant associations between sleep traits and three NHL subtypes (FL, MCL, WM/LPL) in European populations. However, we observed potential influences of chronotype, long and short sleep, and insomnia on NHL risk. These findings align with and extend previous MR study by providing subtype-specific insights. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses using the InterLymph population. These efforts aim to further elucidate the complex relationship between sleep characteristics and NHL risk across diverse subtypes and populations.

Abstract Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10−8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Abstract 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.

Abstract Background The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. Methods We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. Results We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Conclusions Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Abstract Background Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. Objective We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. Methods We used individual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. Results We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). Conclusions We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Abstract Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 [odds ratio (OR) = 0.71, P = 4.29×10−8); rs79942605 (OR = 2.17, P = 2.81×10−8) and rs208908 (OR = 0.70, P = 4.54×10−8) were identified with different risk effect of lung cancer between men and women. Further expression quantitative trait loci and functional annotation analysis suggested rs208908 affects lung cancer risk through differential regulation of Coxsackie virus and adenovirus receptor gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.