Cell-free DNA methylation-based inflammation score as a marker for hepatocellular carcinoma among people living with HIV

Background: People living with the human immunodeficiency virus (HIV) are at a greater risk of developing hepatocellular carcinoma (HCC), potentially due to the stimulation of inflammation by HIV infection. Inflammation-related DNA methylation signatures obtained in liquid biopsy, such as circulating cell-free DNA (cfDNA), may serve as promising minimally invasive biomarkers that can inform diagnosis of HCC.

Methods: Using data from 249 individuals with HIV (114 individuals with normal liver conditions, 69 with fibrosis, 30 with cirrhosis, and 36 with HCC), we constructed a cfDNA methylation-based inflammation score (inflammation-DNAm score) based on 54 CpGs previously associated with circulating C-reactive protein concentrations. Associations of DNAm scores with HCC were assessed using multivariable logistic regression models. Receiver operating characteristic analysis was conducted to assess the performance of discriminating HCC between the inflammation-DNAm score and alpha-fetoprotein (AFP), one of the current screening biomarkers.

Results: A higher inflammation-DNAm score was associated with a 29% increase in the odds of HCC (OR = 1.29, 95% CI = 1.01-1.65). The association remained consistent in the models adjusted for cellular origin proportions. The DNAm score exhibited superior performance in discriminating HCC from controls (AUC = 0.94, 95% CI = 0.90-0.98), compared to AFP (AUC = 0.68, 95% CI = 0.51-0.85).

Conclusions: Our findings suggest that cfDNA methylation-based biomarkers may aid in the detection of HCC in people living with HIV, a population at high-risk of developing HCC.