Methylation Changes in Viral and Host DNA in Blood as Biomarkers for Early Detection of Lymphomagenesis in HIV-Infected Individuals

People living with HIV face a significantly higher risk of developing non-Hodgkin’s lymphoma (NHL), which is the leading cause of cancer-related death in this population in the USA. Although the introduction of combination antiretroviral therapy has significantly decreased the incidence of NHL among PWH, it remains much higher than in the general population. Furthermore, individuals with HIV tend to be diagnosed with later-stage NHL and have worse prognoses than those without HIV. Thus, developing an effective strategy for earlier detection of NHL before symptomatic presentation, when cure rates are higher, is an especially important priority for people with HIV. This proposal aims to develop and validate a blood test to enable earlier detection of non-Hodgkin’s lymphoma in people with HIV, with the ultimate goal of improving NHL-survival rates in this population. We will measure altered methylation patterns of tumor-derived cell-free DNA (cfDNA) fragments in blood as biomarkers of lymphomagenesis. Specifically, we will noninvasively evaluate the hypermethylation of Epstein-Barr Virus (EBV) DNA and of gene promoters in infected B cell genomes which arise during the development of diffuse large B-cell lymphoma in people with HIV. This project is made possible by a liquid biopsy technology developed by our group, which permits efficient and comprehensive genome-wide profiling of hypermethylation patterns in cell-free DNA fragments derived from tumor cells. With access to crucial longitudinally banked plasma samples from a large cohort study of people with HIV, we are well-poised to evaluate changes in methylation of EBV DNA and the host B cell genome that occur prior to symptomatic diagnosis of lymphoma. Initial data indicate the assay's ability to detect lymphoma-specific methylation signals in pre-diagnosis plasma, often more than a year before diagnosis. This project will extend the analysis to a larger dataset, aiming to develop a predictive algorithm for early NHL detection. Key aims include characterizing the temporal order of methylation changes, evaluating algorithm sensitivity and specificity, and developing a longitudinal test to track personalized methylation signals over time. Ultimately, the project aims to develop an effective and practical approach for earlier detection of NHL, thereby improving clinical outcomes in people living with HIV. Project Number: 1R01CA306526-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Abhijit Patel (+1 co-PI) | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $677,621 | Activity Code: R01 | Study Section: HIV Coinfections and HIV Associated Cancers Study Section[HCAC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11328500