Validation of a liquid biopsy assay for early detection of lymphoma in people with HIV

The National Cancer Institute awarded Yale University a $279,018 cooperative agreement on September 1, 2026, to validate a liquid biopsy assay for early detection of non-Hodgkin's lymphoma in people living with HIV under the Cancer Detection and Diagnosis Research program (CFDA 93.394).

The project conducts analytical and clinical validation of a high-density methyl-seq assay that detects gene silencing patterns associated with NHL through promoter methylation events in circulating cell-free DNA. Preliminary studies show the assay can detect NHL-specific methylation signals up to one year before clinical diagnosis in individuals with HIV. Using pre-diagnosis plasma samples from the NIH-sponsored MACS/WIHS Combined Cohort Study, the research aims to establish sensitivity and specificity thresholds necessary for clinical adoption as a screening tool for NHL in this elevated-risk population, where late-stage diagnoses and aggressive disease phenotypes currently drive poor prognosis despite improvements in overall survival from antiretroviral therapy.

Work is performed in New Haven, Connecticut, with a period of performance through August 31, 2028.

Abstract

This project seeks to validate a liquid biopsy assay to enable effective screening of non-hodgkin's lymphoma (NHL) in people living with HIV (PWH), a population that experiences a significantly higher incidence of NHL, along with a notably poorer prognosis due to late-stage diagnoses. Despite improvements in the overall survival of PWH due to combination antiretroviral therapy, NHL remains a leading cause of cancer-related death within this group, and the majority of cases are diagnosed at advanced stages with aggressive phenotypes and extra- nodal involvement. Early detection of NHL is crucial to improving clinical outcomes in PWH, yet there currently exists no effective screening paradigm in this elevated-risk population. To address this GAP, the project focuses on validating a novel liquid biopsy assay, high density methyl-SEQ, which detects global gene silencing patterns associated with NHL through promoter methylation events in circulating cell-free DNA. This technology has shown compelling results in preliminary studies, detecting NHL-specific methylation signals up to one year before diagnosis in individuals with HIV. Using a unique collection of pre-diagnosis plasma samples from the NIH- sponsored macs/wihs combined cohort study, this project will conduct both analytical and clinical validation of the assay, ensuring that IT meets the rigorous standards necessary for clinical adoption. By confirming the assay's sensitivity and specificity for detecting NHL before symptomatic presentation, the project aims to establish an effective screening tool for NHL in PWH, with the potential to significantly improve early diagnosis, treatment, and survival outcomes for this vulnerable population.