Circulating cell‐free <scp>DNA</scp> methylation biomarkers for hepatocellular carcinoma risk prediction in <scp>HIV</scp> ‐positive Nigerian population

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, with particularly high burdens among people living with HIV (PLWH) in low-resource settings like Nigeria. Effective early detection remains a major challenge due to limited access to imaging-based surveillance and the low sensitivity of current biomarkers such as alpha-fetoprotein (AFP). We conducted an epigenome-wide association study (EWAS) of circulating cell-free DNA (ccfDNA) methylation in a Nigerian cohort of HIV-positive individuals (n = 245), spanning HCC, cirrhosis (FibroScan ≥12.3 kPa), fibrosis (FibroScan ≥7.6 and <12.3 kPa), and HCC-free without fibrosis (FibroScan <7.6 kPa) groups. Using random forest modeling, we developed and evaluated a ccfDNA methylation classifier (ccfDNAmRF) for HCC risk prediction. We identified 73 CpG sites significantly associated with HCC (false discovery rate <0.01). The ccfDNAmRF model demonstrated strong discriminatory power, achieving 100% sensitivity and 80%-91% specificity for distinguishing HCC from cirrhosis, fibrosis, and HCC-free groups (area under the curve [AUC]: 92%-97%). Combining ccfDNA methylation risk scores with AFP further improved classification accuracy (AUC up to 98.5%). Notably, ccfDNA methylation patterns displayed clear dose-response relationships across the disease spectrum, supporting their utility for early-stage detection and risk stratification. Our findings highlight the promise of ccfDNA methylation biomarkers as a non-invasive, blood-based screening tool for improving early identification of HCC cases among PLWH.

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Publication Details

Journal
International Journal of Cancer
Published
2025-10-23
DOI
https://doi.org/10.1002/ijc.70204
Primary Topic
Epigenetics and DNA Methylation
Type
article
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article

Circulating cell‐free DNA methylation biomarkers for hepatocellular carcinoma risk prediction in HIV ‐positive Nigerian population

Jingzhe Han, Lifang Hou, Nicola D. Roberts, Godwin Imade et al.
International Journal of Cancer
Epigenetics and DNA Methylation
article

Circulating cell‐free DNA methylation biomarkers for hepatocellular carcinoma risk prediction in HIV ‐positive Nigerian population

Jingzhe Han, Lifang Hou, Nicola D. Roberts, Godwin Imade, Claudia Hawkins, Olugbenga A. Silas, Ganiyat K. Oyeleke, FB Abdulkareem, Yishu Qu, Emuobor Odeghe, Pantong Davwar, Robert L. Murphy, Yinan Zheng, Atiene S. Sagay, Demirkan Gursel, Olufunmilayo Lesi, Folasade Ogunsola, Brian Joyce, Kwang‐Youn A. Kim, Jian‐Jun Wei, Hushan Yang, Chad J. Achenbach, Jun Wang, Xuehong Zhang, Zequn Sun, David Nyam, Masha Kocherginsky, Akanmu A. Sulaimon, Mary Duguru, Kabir Badmos, Edith Nonyelum Okeke
article en

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally, with particularly high burdens among people living with HIV (PLWH) in low-resource settings like Nigeria. Effective early detection remains a major challenge due to limited access to imaging-based surveillance and the low sensitivity of current biomarkers such as alpha-fetoprotein (AFP). We conducted an epigenome-wide association study (EWAS) of circulating cell-free DNA (ccfDNA) methylation in a Nigerian cohort of HIV-positive individuals (n = 245), spanning HCC, cirrhosis (FibroScan ≥12.3 kPa), fibrosis (FibroScan ≥7.6 and <12.3 kPa), and HCC-free without fibrosis (FibroScan <7.6 kPa) groups. Using random forest modeling, we developed and evaluated a ccfDNA methylation classifier (ccfDNAmRF) for HCC risk prediction. We identified 73 CpG sites significantly associated with HCC (false discovery rate <0.01). The ccfDNAmRF model demonstrated strong discriminatory power, achieving 100% sensitivity and 80%-91% specificity for distinguishing HCC from cirrhosis, fibrosis, and HCC-free groups (area under the curve [AUC]: 92%-97%). Combining ccfDNA methylation risk scores with AFP further improved classification accuracy (AUC up to 98.5%). Notably, ccfDNA methylation patterns displayed clear dose-response relationships across the disease spectrum, supporting their utility for early-stage detection and risk stratification. Our findings highlight the promise of ccfDNA methylation biomarkers as a non-invasive, blood-based screening tool for improving early identification of HCC cases among PLWH.

International Journal of CancerVol. 158(5)
Northwestern University (US), Mayo Clinic (US), Thomas Jefferson University (US), University of Jos (NG), University of Lagos (NG), Yale University (US), University of New Haven (US)
Openalex Percentile: Top 73%
Epigenetics and DNA Methylation
DOIOpen Access PDFOpenAlex
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