Byun, Jinyoung

Abstract Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Prognostic models for HCC primarily rely on tumor burden and liver function, with limited consideration of inherited genetic contributions to survival variability. Identifying germline variants associated with survival could refine prognosis and reveal biological mechanisms underlying disease progression. Methods: We conducted a genome-wide association study (GWAS) of overall survival among 864 patients with HCC from the M.D. Anderson Cancer Center cohort. Genotyping, quality control, and imputation procedures followed previously described protocols (PMID: 38381705). Associations between genetic variants and overall survival were assessed using Cox proportional hazards models adjusted for age, sex, and the first five principal components. Genome-wide significance was defined as P < 5×10-8. Functional annotation and pathway enrichment analyses (MAGMA) were employed to investigate the biological relevance of the identified loci. Results: After quality control, 8,525,017 single-nucleotide polymorphisms (SNPs) were analyzed. We identified seven new loci associated with HCC survival at the genome-wide significance level. Five out of seven loci are associated with anthropometric traits and hematological measurement traits, reflecting metabolism, hematopoiesis, immune function, and inflammation. A variant in the 3′ untranslated region (UTR3) of STX7 showed a genome-wide significant association with overall survival (HR = 3.23; P = 2.56 ×10-8). Carriers of the risk allele had significantly shorter survival times compared with noncarriers. Pathway analysis revealed enrichment in biologically relevant processes, including liver growth and regeneration (growth hormone and Interleukin-6 (IL-6) signaling pathway), implicating hepatocyte proliferation and IL-6/STAT3-mediated inflammatory signaling. Immune-related pathways, such as regulation of T cell activation and myeloid leukocyte migration, highlight the role of germline variation in immune surveillance. Moreover, pathways governing vascular remodeling and metabolic stress response (e.g., JAK activation, mitochondrial dynamics) suggest that inherited determinants of microenvironmental structure and hepatocyte resilience influence patient outcomes. Conclusion: This germline GWAS of HCC survival identifies seven new genome-wide significant loci and implicates pathways involved in liver regeneration, inflammation, and tissue remodeling. These findings support a role for inherited genetic variation in shaping HCC prognosis and underscore the potential of integrating germline genetics into prognostic modelling and therapeutic target discovery. Citation Format: Younghun Han, Jinyoung Byun, Lewis R. Roberts, Katherine A. McGlynn, Manal M. Hassan, Christopher I. Amos. Identification of survival-associated germline variants in hepatocellular carcinoma [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 3606.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome‐wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co‐development with hepatitis C virus‐negative (HCV‐negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV‐negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV‐negative HCC and blood‐based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV‐negative HCC and diseases associated with metabolic dysfunction‐associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood‐based biomarkers identified in this study for inferring HCC development among HCV‐negative individuals.

Abstract Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of non-viral liver diseases. Genome-wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co-development with non-viral HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between non-viral HCC with 923 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB) cohort. We observed a SNP-array heritability (h2 obs) of 0.20 for non-viral HCC. Next, we estimated the pairwise genetic correlation between non-viral HCC and heritable (h2 obs &gt; 0.02) UKBB traits, identifying significant positive genetic correlations between non-viral HCC and blood-based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between non-viral HCC and diseases associated with metabolic dysfunction-associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Non-viral HCC was negatively associated with filtered coffee intake but positively associated with instant coffee intake. In addition, smoking behavior and the amount of alcohol consumption in the UKBB cohort showed a positive association with non-viral HCC. Our study provides an atlas of cross-trait genetic correlations in non-viral HCC. Taken together, our results demonstrate possible polygenic pleiotropy between non-viral HCC and different phenotypic traits. The results support further exploration of the predictive power of blood-based biomarkers and selected behaviors for inferring HCC development among non-viral individuals. Citation Format: Younghun Han, Vikram Shaw, Jinyoung Byun, Rikita Hatia, Katherine McGlynn, Lewis Roberts, Manal Hassan, Christopher I. Amos. Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits [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 2284.

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 &lt; 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 &lt; 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.

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP, rs9842969, (0.51, [0.40–0.65]); 5p15.33, TERT, rs2242652, (0.70, (0.62–0.79]); 19q13.11, TM6SF2, rs58542926, (1.49, [1.29–1.72]); 19p13.11 MAU2, rs58489806, (1.53, (1.33–1.75]); and 22q13.31, PNPLA3, rs738409, (1.66, [1.51–1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74–0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

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 &lt; 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 &gt; 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 Cholangiocarcinoma (CCA) is a rare and aggressive cancer of the bile ducts, with a poor prognosis and limited treatment options. CCA are classified as intrahepatic and extrahepatic based on anatomical location. CCA are often diagnosed at an advanced stage because there are no effective tools for early detection. Although genome-wide association studies (GWASs) have discovered many genome-wide significant contributing risk loci, the genetic underpinning of cholangiocarcinoma remains poorly understood. To date, there is no cholangiocarcinoma-specific GWAS. We conducted GWAS of cholangiocarcinoma in 9,648 individuals of European ancestry using TOPMed reference panel. The putative associations in or near THSD7A on chromosome 7 (OR=2.61, P=7.13 × 10−8), ZBTB16 on 11 (OR=0.16, P=6.02 × 10−8) for non-PSC-related CCA, PUM3 on 9 (OR=10.74, P=6.12 × 10−8), AGBL1 on 15 (OR=2.08, P=5.67 × 10−8) for PSC-related CCA, and LINC02506 on 4 (OR=0.16, P=8.83 × 10−9) for extrahepatic CCA. We also implemented linkage disequilibrium score regression (LDSR) analysis to quantify the genetic correlation between phenotypes using publicly available GWAS summary statistics. Our study aimed to identify possible clinical and epidemiological traits associated with CCA. We identified numerous biomarkers, medical conditions, environmental and behavioral traits, and physical measurements showing high heritability, which is the proportion of phenotypic variance explained by all SNPs included in the analysis, and pairwise genetic correlation with CCA and other CCA subtypes. Elevations of selected biomarkers such as alkaline phosphatase, cystatin C, HbA1c, monocyte count, and white blood cell count show a positive genetic association with CCA in European-ancestry population. Also, autoimmune-mediated conditions show a strong positive genetic association with CCA, non-PSC related CCA, and intrahepatic CCA. The GWAS of CCA and CCA subtypes revealed potential genetic susceptibility associations and will allow us to compare the genetic architecture underlying CCA and other diseases of the bile ducts such as primary sclerosing cholangitis and liver cancer. LDSR provided an improved understanding of the genetic architecture between CCA and potential comorbid conditions and biomarkers. Mendelian randomization analysis will be needed to elucidate the causal relationship between CCA and traits of interest. Citation Format: Younghun Han, Katherine A. McGlynn, Jinyoung Byun, Matthew A. Cooley, Manal M. Hassan, Christopher I. Amos, Lewis R. Roberts, The International Consortium for the Genetics of Biliary Tract Cancers. Genome-wide association study and LD score regression analysis for cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5228.

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 &lt; 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.