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

Kyeezu Kim; Yinan Zheng; Brian T. Joyce; Drew R. Nannini; Jun Wang; Yishu Qu; Claudia A. Hawkins; Edith Okeke; Olufunmilayo A. Lesi; Lewis R. Roberts; Demirkan B. Gursel; Fatimah B. Abdulkareem; Alani S. Akanmu; Mary J. Duguru; Pantong Davwar; David Paul Nyam; Rahmat A. Adisa; Godwin Imade; Jian Jun Wei; Masha Kocherginsky; Kwang Youn Kim; Wasiu L. Adeyemo; Emuobor Odeghe; Firas H. Wehbe; Chad Achenbach; Atiene Sagay; Folasade Ogunsola; Robert L. Murphy; Lifang Hou

doi:10.1007/s12072-024-10768-1

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

Kyeezu Kim^*, Yinan Zheng, Brian T. Joyce, Drew R. Nannini, Jun Wang, Yishu Qu, Claudia A. Hawkins, Edith Okeke, Olufunmilayo A. Lesi, Lewis R. Roberts, Demirkan B. Gursel, Fatimah B. Abdulkareem, Alani S. Akanmu, Mary J. Duguru, Pantong Davwar, David Paul Nyam, Rahmat A. Adisa, Godwin Imade, Jian Jun Wei, Masha KocherginskyKwang Youn Kim, Wasiu L. Adeyemo, Emuobor Odeghe, Firas H. Wehbe, Chad Achenbach, Atiene Sagay, Folasade Ogunsola, Robert L. Murphy, Lifang Hou^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	e0282539
Journal	Hepatology International
DOIs	https://doi.org/10.1007/s12072-024-10768-1
State	Accepted/In press - 2024

Funding

This study was supported by funding from the Division of Cancer Prevention, National Cancer Institute (Grant Number: NIH/NCI U54CA221205; PIs: Robert Murphy, Lifting Hou). This study is also partially supported by the National Research Foundation of South Korea, funded by the Ministry of Science and Technology (Grant Number: RS-2024-00405650). The funders of the current study had no role in study design, conduct of the study, data collection and analysis, interpretation of the results, manuscript preparation, review, and approval, or decision to manuscript submission for publication.

Keywords

C-reactive protein
Cell-free DNA methylation
Hepatocellular carcinoma
Methylation risk score
Methylation-based inflammation measures

ASJC Scopus subject areas

Hepatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s12072-024-10768-1

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Kim, K., Zheng, Y., Joyce, B. T., Nannini, D. R., Wang, J., Qu, Y., Hawkins, C. A., Okeke, E., Lesi, O. A., Roberts, L. R., Gursel, D. B., Abdulkareem, F. B., Akanmu, A. S., Duguru, M. J., Davwar, P., Nyam, D. P., Adisa, R. A., Imade, G., Wei, J. J., ... Hou, L. (Accepted/In press). Cell-free DNA methylation-based inflammation score as a marker for hepatocellular carcinoma among people living with HIV. Hepatology International, Article e0282539. https://doi.org/10.1007/s12072-024-10768-1

@article{09ffa23e2fc94c70a4d69e35aafe2227,

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

abstract = "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.",

keywords = "C-reactive protein, Cell-free DNA methylation, Hepatocellular carcinoma, Methylation risk score, Methylation-based inflammation measures",

author = "Kyeezu Kim and Yinan Zheng and Joyce, {Brian T.} and Nannini, {Drew R.} and Jun Wang and Yishu Qu and Hawkins, {Claudia A.} and Edith Okeke and Lesi, {Olufunmilayo A.} and Roberts, {Lewis R.} and Gursel, {Demirkan B.} and Abdulkareem, {Fatimah B.} and Akanmu, {Alani S.} and Duguru, {Mary J.} and Pantong Davwar and Nyam, {David Paul} and Adisa, {Rahmat A.} and Godwin Imade and Wei, {Jian Jun} and Masha Kocherginsky and Kim, {Kwang Youn} and Adeyemo, {Wasiu L.} and Emuobor Odeghe and Wehbe, {Firas H.} and Chad Achenbach and Atiene Sagay and Folasade Ogunsola and Murphy, {Robert L.} and Lifang Hou",

note = "Publisher Copyright: {\textcopyright} Asian Pacific Association for the Study of the Liver 2024.",

year = "2024",

doi = "10.1007/s12072-024-10768-1",

language = "English (US)",

journal = "Hepatology International",

issn = "1936-0533",

publisher = "Springer",

}

Kim, K, Zheng, Y , Joyce, BT, Nannini, DR, Wang, J, Qu, Y, Hawkins, CA, Okeke, E, Lesi, OA, Roberts, LR, Gursel, DB, Abdulkareem, FB, Akanmu, AS, Duguru, MJ, Davwar, P, Nyam, DP, Adisa, RA, Imade, G, Wei, JJ , Kocherginsky, M, Kim, KY, Adeyemo, WL, Odeghe, E, Wehbe, FH, Achenbach, C, Sagay, A, Ogunsola, F, Murphy, RL & Hou, L 2024, 'Cell-free DNA methylation-based inflammation score as a marker for hepatocellular carcinoma among people living with HIV', Hepatology International. https://doi.org/10.1007/s12072-024-10768-1

TY - JOUR

T1 - Cell-free DNA methylation-based inflammation score as a marker for hepatocellular carcinoma among people living with HIV

AU - Kim, Kyeezu

AU - Zheng, Yinan

AU - Joyce, Brian T.

AU - Nannini, Drew R.

AU - Wang, Jun

AU - Qu, Yishu

AU - Hawkins, Claudia A.

AU - Okeke, Edith

AU - Lesi, Olufunmilayo A.

AU - Roberts, Lewis R.

AU - Gursel, Demirkan B.

AU - Abdulkareem, Fatimah B.

AU - Akanmu, Alani S.

AU - Duguru, Mary J.

AU - Davwar, Pantong

AU - Nyam, David Paul

AU - Adisa, Rahmat A.

AU - Imade, Godwin

AU - Wei, Jian Jun

AU - Kocherginsky, Masha

AU - Kim, Kwang Youn

AU - Adeyemo, Wasiu L.

AU - Odeghe, Emuobor

AU - Wehbe, Firas H.

AU - Achenbach, Chad

AU - Sagay, Atiene

AU - Ogunsola, Folasade

AU - Murphy, Robert L.

AU - Hou, Lifang

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - C-reactive protein

KW - Cell-free DNA methylation

KW - Hepatocellular carcinoma

KW - Methylation risk score

KW - Methylation-based inflammation measures

UR - http://www.scopus.com/inward/record.url?scp=85212477659&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85212477659&partnerID=8YFLogxK

U2 - 10.1007/s12072-024-10768-1

DO - 10.1007/s12072-024-10768-1

M3 - Article

C2 - 39704909

AN - SCOPUS:85212477659

SN - 1936-0533

JO - Hepatology International

JF - Hepatology International

M1 - e0282539

ER -

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

Abstract

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UN SDGs

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