Abstract B012: Advanced epigenetic aging in non-AIDS-defining cancer patients living with HIV

Abstract

Abstract Background. With widespread use of antiretroviral therapy, people with HIV (PWH) are living longer and are now at risk for age-related co-morbidities, including non-AIDS defining cancers (NADCs). Given this epidemiological trend, it is important to understand how prolonged HIV infection may relate to molecular features of aging that can impact cancer risk or outcomes. Methyl groups naturally accumulate on human DNA over time, and methylation patterns can be translated into metrics of accelerated aging. We compared epigenetic measures of aging between PWH receiving treatment for an NADC and matched HIV-uninfected NADC patients at Moffitt Cancer Center in Tampa, Florida. Methods. We identified PWH diagnosed with a non-AIDS defining solid tumor from 2004 to 2021 were identified. To be included, patients needed to have an archived specimen amenable for DNA extraction (whole blood, buffy coat, or PBMC) collected within 1 year of cancer diagnosis. HIV-uninfected matches were identified in a similar manner and matched by tumor site, reported age (+/- 5 years), tumor sequence (primary vs. non-primary), and treatment status. Extracted DNA was assayed using the Illumina MethylationEPIC BeadChip, which incorporates data from 850,000 CpG sites across the genome. Data were translated into a biological age using the epiTOC2 clock, which estimates the number of total number of stem cell divisions, and GrimAge, associated with mortality. Methylation data were also deconvoluted to determine immune cell composition (CD4+ T-cells, CD8+ T-cells, B-cells, neutrophils, natural killer cells, monocytes, basophils, eosinophils). Epigenetic age and immune cell proportions were compared across HIV status using Wilcoxan rank sum testing. Age acceleration was calculated as the difference (residuals from a linear model) in the observed age for PWH and a NADC diagnosis, compared to the predicted age based on HIV-uninfected NADC patients, using both unadjusted and immune-cell adjusted linear models. Results. DNA methylation was assessed in 65 NADC PWH and HIV and 64 HIV-uninfected NADC patients. Epigenetic age assessed using the epiTOC2 and GrimAge clocks was significantly elevated in PWH (p<0.001 and p=0.02, respectively). When methylation data was used to de-convolute immune cell composition, the proportion of CD4+ T-cells and neutrophils was significantly (P<0.05) lower in PWH, while the proportions of memory B-cells and CD8+ T-cells were higher. Epigenetic age was accelerated in PWH compared to HIV-uninfected patients using both epiTOC2 and GrimAge clocks, with the difference in the GrimAge clock remaining significant after adjustment for immune cell composition (P-value<0.01). Conclusions. The results of this study demonstrated age acceleration in PWH with a NADC diagnosis compared to their HIV-uninfected counterparts. As cancer is now the leading cause of non-AIDS death in PWH, research into the prognostic implications of these differences is warranted. Citation Format: Anna E. Coghill, Brittney Dickey, Ryan Putney, Anders Berglund. Advanced epigenetic aging in non-AIDS-defining cancer patients living with HIV [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B012.