Genome-wide association study of HBV-related hepatocellular carcinoma identifies a functional variant at the FAM114A1 locus

Liver cancer ranks sixth in cancer incidence and third in cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the primary histological subtype, and hepatitis B virus (HBV) carriers have a higher risk of HCC. Although several susceptibility loci for HCC have been identified in East Asian populations through genome-wide association studies (GWAS), the underlying biological mechanisms of this malignancy remain incompletely understood. Here, we conduct a two-stage GWAS including 2413 cases and 2794 HBV-positive controls from a high-incidence region in Southern China. The function of the susceptibility locus is investigated by bioinformatic and experimental approaches, supported by a xenograft model. We identify a 4p14 locus significantly associated with the risk of HCC (rs55718051, OR [95 % CI] = 0.73 [0.67-0.80], P<sub>meta</sub> = 9.14 × 10<sup>-11</sup>), and 18q23 locus with borderline significance (rs12964643: OR [95 % CI] = 0.75 [0.67-0.83], P<sub>meta</sub> = 1.11 × 10<sup>-7</sup>). Functional experiments indicate the role of rs55718051 in FAM114A1 expression regulation, possibly through the interaction with FOXA1. Knockdown of FAM114A1 significantly enhances the oncogenic phenotypes in liver cancer cells, suggesting its potential tumor suppressor role. Our findings expand the understanding of HCC susceptibility and suggest FAM114A1 as a potential suppressor in HBV-related HCC carcinogenesis.

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Journal
Journal of genetics and genomics/Journal of Genetics and Genomics
Published
2025-11-01
DOI
https://doi.org/10.1016/j.jgg.2025.11.003
Citations
1
Primary Topic
NF-κB Signaling Pathways
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article
Field-Weighted Citation Impact
0.94
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article

Genome-wide association study of HBV-related hepatocellular carcinoma identifies a functional variant at the FAM114A1 locus

Rui Guo, Yuan Yang, Yanji Jiang, Tianyi Zhu et al.
1 citations
Journal of genetics and genomics/Journal of Genetics and Genomics
NF-κB Signaling Pathways
0.94
article

Genome-wide association study of HBV-related hepatocellular carcinoma identifies a functional variant at the FAM114A1 locus

Rui Guo, Yuan Yang, Yanji Jiang, Tianyi Zhu, Zihan Zhou, Ruoxin Zhang, Min Ji, Qiuping Wen, Gangqiao Zhou, Bang‐De Xiang, Yuanfeng Li, Qiuling Lin, Shicheng Zhan, Litu Zhang, Hongliang Liu, Liang Ma, Jiao Wang, Hongping Yu, Yingchun Liu, Ziliang Wang, Shengping Li, Ji Zheng, Xiaoqiang Qiu, Mengyun Wang, Xiaoyun Zeng, Weizhong Tang, Binbin Jiang, Juncheng Dai, Wen‐Feng Gong, Junjie Wei, Qingyi Wei, Shanshan Liu
article en
1 citations

Abstract

Liver cancer ranks sixth in cancer incidence and third in cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the primary histological subtype, and hepatitis B virus (HBV) carriers have a higher risk of HCC. Although several susceptibility loci for HCC have been identified in East Asian populations through genome-wide association studies (GWAS), the underlying biological mechanisms of this malignancy remain incompletely understood. Here, we conduct a two-stage GWAS including 2413 cases and 2794 HBV-positive controls from a high-incidence region in Southern China. The function of the susceptibility locus is investigated by bioinformatic and experimental approaches, supported by a xenograft model. We identify a 4p14 locus significantly associated with the risk of HCC (rs55718051, OR [95 % CI] = 0.73 [0.67-0.80], P<sub>meta</sub> = 9.14 × 10<sup>-11</sup>), and 18q23 locus with borderline significance (rs12964643: OR [95 % CI] = 0.75 [0.67-0.83], P<sub>meta</sub> = 1.11 × 10<sup>-7</sup>). Functional experiments indicate the role of rs55718051 in FAM114A1 expression regulation, possibly through the interaction with FOXA1. Knockdown of FAM114A1 significantly enhances the oncogenic phenotypes in liver cancer cells, suggesting its potential tumor suppressor role. Our findings expand the understanding of HCC susceptibility and suggest FAM114A1 as a potential suppressor in HBV-related HCC carcinogenesis.

Journal of genetics and genomics/Journal of Genetics and Genomics
Sun Yat-sen University (CN), Guangxi Medical University (CN), Second Military Medical University (CN), Fudan University (CN), Fudan University Shanghai Cancer Center (CN), Shanghai University of Traditional Chinese Medicine (CN), Shanghai Public Health Clinical Center (CN), Ministry of Education (KR), Precision for Medicine (United States) (US), Jiangsu Cancer Hospital (CN), Shanghai Traditional Chinese Medicine Hospital (CN), Eastern Hepatobiliary Surgery Hospital (CN), Sun Yat-sen University Cancer Center (CN), Beijing Proteome Research Center (CN), Tumor Hospital of Guangxi Medical University (CN), Hebei University (CN)
Openalex Percentile: Top 19%
NF-κB Signaling Pathways
0.94
DOIOpen Access PDFOpenAlex
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