Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma

Xinyuan Zhang; Longgang Zhao; Long H Ngo; Simon T Dillon; Xuesong Gu; Michelle Lai; Tracey G Simon; Andrew T Chan; Edward L Giovannucci; Towia A Libermann; Xuehong Zhang

doi:10.1093/jnci/djae079

Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma

J Natl Cancer Inst. 2024 May 1:djae079. doi: 10.1093/jnci/djae079. Online ahead of print.

Authors

Xinyuan Zhang¹, Longgang Zhao^{1

2}, Long H Ngo^{3

4}, Simon T Dillon^{3

5}, Xuesong Gu^{3

5}, Michelle Lai⁶, Tracey G Simon^{7

8}, Andrew T Chan^{1

7

8

9

10}, Edward L Giovannucci^{11

12}, Towia A Libermann^{3

5}, Xuehong Zhang^{1

11

13}

Affiliations

¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
³ Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁵ Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁶ Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁷ Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁰ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ Yale University School of Nursing, Orange, CT, USA.

PMID: 38688524
DOI: 10.1093/jnci/djae079

Abstract

Objective: Proteomics may discover pathophysiological changes related to hepatocellular carcinoma (HCC), an aggressive and lethal type of cancer with low sensitivity for early-stage diagnosis.

Design: We measured 1,305 pre-diagnostic (median 12.7 years) SOMAscan proteins from 54 pairs of healthy individuals who subsequently developed HCC and matched non-HCC controls from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP).

Results: In NHS/HPFS, we identified 56 elevated proteins in HCC with absolute fold-change >1.2 and Wald test P < .05 in conditional logistic regression analysis. Ingenuity Pathway Analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins, chitinase-3-like protein 1, growth/differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin, showed strong positive associations with HCC and were thus validated by ELISA (odds ratio ranged 2.48-14.7, all P < .05) in the NHS/HPFS and by Olink platform (hazard ratio ranged 1.90-3.93, all P < .05) in the UKB-PPP. Adding these four proteins to a logistic regression model of traditional HCC risk factors increased the area under the curve (AUC) from 0.67 to 0.87 in the NHS/HPFS. Consistently, model AUC was 0.88 for HCC risk prediction in the UKB-PPP.

Conclusion: However, the limited number of HCC cases in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

Keywords: CHI3L1; GDF15; Hepatocellular carcinoma; IL1RN; SELE; proteomics.