Perkin, Alani

ABSTRACT Introduction Hepatocellular carcinoma (HCC) development in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) is a growing health concern, but the underlying mechanisms are not fully understood. Epigenetic aging biomarkers, reflecting cellular and tissue aging, have been linked to various age‐related pathologies, but their association with MASLD‐HCC is unknown. We investigated associations between five epigenetic aging biomarkers and MASLD‐HCC risk. Methods We performed whole blood DNA methylation assay (Infinium 850k array) and calculated principal components‐based (PC) versions of HorvathAge, HannumAge, PhenoAge and GrimAge and the DunedinPACE aging rate. We further calculated relative age accelerations for PCHorvathAge, PCHannumAge, PCPhenoAge and PCGrimAge. The aging biomarkers were modelled as continuous variables and categorised into tertiles based on distributions among controls. Associations between each aging biomarker and MASLD‐HCC were examined using logistic regression, calculating odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for covariates. Results Data on 272 MASLD‐HCC cases and 316 cancer‐free MASLD controls recruited from six sites and matched on chronological age, sex and study site were analysed. Higher relative age accelerations of PCPhenoAge (OR T3 vs. T1 = 2.25, 95% CI: 1.45–3.50; OR continuous = 1.04, 95% CI: 1.02–1.07, p = 0.009), PCGrimAge (OR T3 vs. T1 = 3.97, 95% CI: 2.41–6.64; OR continuous = 1.16, 95% CI: 1.10–1.24, p = 8.76 × 10 −07 ) and DunedinPACE (OR T3 vs. T1 = 3.45, 95% CI: 2.17–5.55; OR continuous = 1.72, 95% CI: 1.43–2.10, p = 2.58 × 10 −08 ) were associated with MASLD‐HCC, but not PCHorvathAge or PCHannumAge. Conclusion Higher relative age accelerations of PCPhenoAge, PCGrimAge and DunedinPACE aging rate are associated with risk of MASLD‐HCC. These aging biomarkers could improve HCC risk assessment and facilitate risk stratification in patients with MASLD.

Abstract Multiple Myeloma (MM) is an incurable plasma cell malignancy that progresses from the precursor condition monoclonal gammopathy of undetermined significance (MGUS). African Americans (AA) have the highest incidence of MGUS and MM of any population group in the U.S., with ∼1.5-2-fold higher age-adjusted incidence than European Americans (EA) for reasons that remain unclear. Despite the increased incidence, MM tumors in AA patients show fewer TP53 deletions/mutations and high-risk cytogenetic features compared to EA patients. Studies also show that, with equal access to care, AA patients have better overall survival (OS) independent of age. Given recent studies demonstrating accelerated biological aging in AA individuals, we hypothesize that immunosenescence that occurs with aging reduces the immune pressure on MM cells, resulting in the increased emergence of less aggressive tumors. To test this, we utilized viably frozen bone marrow samples from the Mayo Clinic Myeloma Biobank. We profiled samples from 128 individuals (N= 53 and 75 AA vs. EA, respectively) with either newly diagnosed MM (NDMM) or treated MM (N= 27 and 38 AA vs. EA, respectively), MGUS (N=18 and 23 AA vs. EA, respectively), or healthy controls (N= 8 and 14 AA vs. EA, respectively) by mass cytometry (CyTOF) (N= 17 MGUS, 55 MM and 22 healthy controls) using the CyTOF Human Immune Profile Assay or by single cell RNA-sequencing (scRNA-seq, N= 24 MGUS/SMM and 10 MM). Profiling of the CD45+ non-tumor lymphocytes by scRNA-seq revealed AA patients exhibited increased T cell populations (odds ratio (OR)=2.3), including a reduction in CD8+ effector memory (OR=0.94) and an increase in CD8+ cytotoxic effector (OR=1.02) in a multivariate model adjusting for age and sex. Analysis by CyTOF confirmed an increase in overall CD3+ T cells (49.5% vs. 35.3%, p=0.0001) including increases in CD8+ terminal effector (9.5% vs. 5.2%, p=0.021) and CD4+ terminal effector T cells (5.5% vs. 2.7%, p=5.7x10^-6) among AA patients, and this difference remained after adjusting for age and sex. Within the CD8+ terminal effector T cells, we also noted increases in CD57+/CD28- senescent T cells, consistent with immune exhaustion that occurs with biological aging. We are currently working to assess whether AA patients with MGUS and MM exhibit accelerated biological aging as measured by frailty index, peripheral senescence associated secretory phenotypes, and PBMC epigenetic clock scores. We plan to extend our analysis of the immune microenvironment to assess patient T cell function ex vivo. Finally, we will evaluate whether MM cells from AA patients exhibit increased sensitivity to control cytotoxic T cell induced cell death in vitro compared to cells from EA patients. The results from this study will allow further understanding of components causing the increased risk for MM development seen in AA individuals. Citation Format: Alani Perkin, Megan Moore Weivoda, Linda Baughn. Immunosenescence driven T-cell remodeling may underlie increased risk of Multiple Myeloma in African Americans [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A051.