McGlynn, Katherine A.

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.

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 Background Diet modulates inflammation and insulin response and may be an important modifiable factor in the primary prevention of hepatocellular carcinoma (HCC) and chronic liver disease (CLD). We developed the empirical dietary inflammatory pattern (EDIP) and empirical dietary index for hyperinsulinemia (EDIH) scores to assess the inflammatory and insulinemic potentials of diet. We prospectively examined the associations of EDIP and EDIH at baseline with the following HCC risk and CLD mortality. Design We followed 485 931 individuals in the National Institutes of Health–American Association of Retired Persons Diet and Health Study since 1995. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Results We confirmed 635 incident HCC cases and 993 CLD deaths. Participants in the highest compared with those in the lowest EDIP quartile had a 1.35 times higher risk of developing HCC (95% CI = 1.08 to 1.70, Ptrend = .0005) and a 1.70 times higher CLD mortality (95% CI = 1.41 to 2.04, Ptrend &lt; .0001). For the same comparison, participants with the highest EDIH were at increased risk of HCC (HR = 1.53, 95% CI = 1.20 to 1.95, Ptrend = .0004) and CLD mortality (HR = 1.72, 95% CI = 1.42 to 2.01, Ptrend &lt; .0001). Similar positive associations of scores with HCC risk and CLD mortality were observed for both women and men. Moreover, individuals in both the highest EDIP and EDIH tertiles had a 92% increased HCC risk (95% CI = 1.43 to 2.58) and 98% increased CLD mortality (95% CI = 1.27 to 3.08) compared with those in both lowest tertiles. Conclusions Our findings suggest that inflammation and hyperinsulinemia are potential mechanisms linking diet to HCC development and CLD mortality.

AbstractDeficient intake of micronutrients involved in one‐carbon metabolism (eg, choline, methionine, vitamin B12 and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under‐investigated in humans. We investigated the association between one‐carbon metabolism‐related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow‐up in the NIH‐AARP study. Dietary intakes and supplement use were ascertained at baseline using a food‐frequency questionnaire. Total intake (diet plus supplements) of the following one‐carbon metabolism‐related micronutrients were calculated: folate, methionine and vitamins B2 (riboflavin), B3 (niacin), B6 and B12. These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16‐year follow‐up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B3 intake was associated with a lower HCC risk (HRQ5 vs Q1 = 0.60; 95% CI = 0.42‐0.85; Ptrend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HRQ5 vs Q1 = 0.32; 95% CI = 0.18‐0.55; Ptrend < .0001). Among participants with >3 years of follow‐up, higher total vitamin B3 intake was again associated with lower risk (HRQ5 vs Q1 = 0.37; 95% CI = 0.20‐0.68; Ptrend = .001), whereas higher total vitamin B6 intake was associated with higher risk (HRQ5 vs Q1 = 2.04; 95% CI = 1.02‐4.07; Ptrend = .04). Restricted cubic spline analyses showed a dose‐response inverse association between total vitamin B3 intake and HCC risk, and dose‐response positive association between total vitamin B6 intake and HCC risk. The study suggests that higher vitamin B3 intake is associated with lower HCC risk, whereas higher vitamin B6 intake is associated with increased risk.