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

Hong-Ping Yu; Bang-De Xiang; Ji Qian; Hongliang Liu; Yuan-Feng Li; Qiuling Lin; Shun Liu; Junjie Wei; Shicheng Zhan; Binbin Jiang; Juncheng Dai; Liang Ma; Litu Zhang; Yingchun Liu; Qiuping Wen; Wenfeng Gong; Shengping Li; Yanji Jiang; Ji Zheng; Tianyi Zhu; Zihan Zhou; Xiaoyun Zeng; Ziliang Wang; Ji-Ao Wang; Rui Guo; Yuan Yang; Qingyi Wei; Gangqiao Zhou; Xiao-Qiang Qiu; Weizhong Tang; Mengyun Wang; Ruoxin Zhang

doi:10.1016/j.jgg.2025.11.003

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

doi: 10.1016/j.jgg.2025.11.003

a Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, China;
b Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi 530021, China;
c Key Cultivated Laboratory of Cancer Molecular Medicine of Guangxi Health Commission, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, China;
d Department of Hepatobiliary Surgery and Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research Center, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, China;
e Cancer Institute, Fudan University Shanghai Cancer Center;
Department of Oncology, Shanghai Medical College;
Fudan University, Shanghai 200032, China;
f Biotech Center, School of Life Sciences, Fudan University, Shanghai 200438, China;
g Institute for Precision Cancer Prevention and Medicine, Greater Bay Area Institutes of Precision Medicine (Guangzhou), Guangzhou 511462, China;
h State Key Laboratory of Medical Proteomics, National Center for Protein Sciences at Beijing, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China;
i Department of Clinical Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, China;
j Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, Guangxi 530021, China;
k Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China;
l Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in south China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China;
m Scientific Research Department, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, China;
n Department of Epidemiology, School of Public Health;
Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai 200032, China;
o Clinical Medicine Transformation Center and Office of Academic Research, Shanghai Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China;
p College of Life Science, Hebei University, Baoding, Hebei 071002, China;
q Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China;
r Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. s Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital;
Guangxi Zhuang Autonomous Region Molecular Medical Engineering Research Center for Cancer, Nanning, Guangxi 530021, China

Funds:

We acknowledge all the participants enrolled in the study and the medical staff who contributed to sample recruitment and data collection. We particularly thank Ji Cao and Hai-Zhou Liu for their contribution and support in this study. This project was funded by the National Science Foundation of China (82460668), the Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation (2024GXNSFDA010040), the Key Research and Development Project of Guangxi, China (AA18221001), the Key Project of Guangxi Natural Science Foundation, China (2018GXNSFDA050012), The 111 Projects (D17011), Shanghai Key Disciplines of Public Health (2023-2025) for New Three-year Action Plan (GWVI11.1-23).

Received Date: 2024-12-22
Accepted Date: 2025-11-07
Rev Recd Date: 2025-11-02

Available Online: 2025-11-14

Abstract

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_meta = 9.14 × 10^-11), and 18q23 locus with borderline significance (rs12964643: OR [95% CI] = 0.75 [0.67–0.83], P_meta = 1.11 × 10^-7). Functional experiments indicate the role of rs55718051 in FAM114A1 expression regulation, possibly through interaction of 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.
- Hepatocellular carcinoma,
- Hepatitis B virus,
- Genome-wide association study,
- Functional variant,
- Cancer susceptibility

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References

Akcay, I.M., Katrinli, S., Ozdil, K., Doganay, G.D., Doganay, L., 2018. Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies. World J. Gastroenterol. 24, 3347-3360.

Barrett, J.C., Fry, B., Maller, J., Daly, M.J., 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263-265.

Boucquey, M., De Plaen, E., Locker, M., Poliard, A., Mouillet-Richard, S., Boon, T., Kellermann, O., 2006. Noxp20 and Noxp70, two new markers of early neuronal differentiation, detected in teratocarcinoma-derived neuroectodermic precursor cells. J. Neurochem. 99, 657-669.

Castro-Mondragon, J.A., Riudavets-Puig, R., Rauluseviciute, I., Lemma, R.B., Turchi, L., Blanc-Mathieu, R., Lucas, J., Boddie, P., Khan, A., Manosalva Perez, N., et al., 2022. JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 50, D165-D173.

Chan, K.Y., Wong, C.M., Kwan, J.S., Lee, J.M., Cheung, K.W., Yuen, M.F., Lai, C.L., Poon, R.T., Sham, P.C., Ng, I.O., 2011. Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection. PloS one 6, e28798.

Cirillo, L.A., McPherson, C.E., Bossard, P., Stevens, K., Cherian, S., Shim, E.Y., Clark, K.L., Burley, S.K., Zaret, K.S., 1998. Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J. 17, 244-254.

Clifford, R.J., Zhang, J., Meerzaman, D.M., Lyu, M.S., Hu, Y., Cultraro, C.M., Finney, R.P., Kelley, J.M., Efroni, S., Greenblum, S.I., et al., 2010. Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology 52, 2034-2043.

Das, S., Forer, L., Schonherr, S., Sidore, C., Locke, A.E., Kwong, A., Vrieze, S.I., Chew, E.Y., Levy, S., McGue, M., et al., 2016. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284-1287.

de Leeuw, C.A., Mooij, J.M., Heskes, T., Posthuma, D., 2015. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219.

Jiang, D.K., Sun, J., Cao, G., Liu, Y., Lin, D., Gao, Y.Z., Ren, W.H., Long, X.D., Zhang, H., Ma, X.P., el al., 2013. Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat. Genet. 45, 72-75.

Kew, M., Francois, G., Lavanchy, D., Margolis, H., Van Damme, P., Grob, P., Hallauer, J., Shouval, D., Leroux-Roels, G., Meheus, A., Viral Hepatitis Prevention, B., 2004. Prevention of hepatitis C virus infection. J. Viral Hepat. 11, 198-205.

Kim, D., Langmead, B., Salzberg, S.L., 2015. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357-360.

Kumar, V., Kato, N., Urabe, Y., Takahashi, A., Muroyama, R., Hosono, N., Otsuka, M., Tateishi, R., Omata, M., Nakagawa, H., et al., 2011. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat. Genet. 43, 455-458.

Langmead, B., Salzberg, S.L., 2012. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357-359.

Lee, M.H., Huang, Y.H., Chen, H.Y., Khor, S.S., Chang, Y.H., Lin, Y.J., Jen, C.L., Lu, S.N., Yang, H.I., Nishida, N., et al., 2017. Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome-wide association study. Hepatology 67, 651-661.

Li, Tuteja, G., Schug, J., Kaestner, K.H., 2012a. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 148, 72-83.

Li, B., Dewey, C.N., 2011. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinf. 12, 323.

Li, S., Qian, J., Yang, Y., Zhao, W., Dai, J., Bei, J.X., Foo, J.N., McLaren, P.J., Li, Z., Yang, J., et al., 2012b. GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers. PLoS Genet. 8, e1002791.

Lin, Y.Y., Yu, M.W., Lin, S.M., Lee, S.D., Chen, C.L., Chen, D.S., Chen, P.J., 2017. Genome-wide association analysis identifies a GLUL haplotype for familial hepatitis B virus-related hepatocellular carcinoma. Cancer 123, 3966-3976.

Liu, Z., Jiang, Y., Yuan, H., Fang, Q., Cai, N., Suo, C., Jin, L., Zhang, T., Chen, X., 2019. The trends in incidence of primary liver cancer caused by specific etiologies: Results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention. J. Hepatol. 70, 674-683.

Matsuura, K., Sawai, H., Ikeo, K., Ogawa, S., Iio, E., Isogawa, M., Shimada, N., Komori, A., Toyoda, H., Kumada, T., et al., 2017. Genome-Wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 152, 1383-1394.

McGlynn, K.A., Petrick, J.L., El-Serag, H.B., 2021. Epidemiology of hepatocellular carcinoma. Hepatology 73 Suppl 1, 4-13.

Miki, D., Ochi, H., Hayes, C.N., Abe, H., Yoshima, T., Aikata, H., Ikeda, K., Kumada, H., Toyota, J., Morizono, T., et al., 2011. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat. Genet. 43, 797-800.

Park, J.G., Lee, J.H., Kang, M.S., Park, K.J., Jeon, Y.M., Lee, H.J., Kwon, H.S., Park, H.S., Yeo, K.S., Lee, K.U., et al., 1995. Characterization of cell lines established from human hepatocellular carcinoma. Int. J. Cancer 62, 276-282.

Parkin, D.M., 2006. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 118, 3030-3044.

Perz, J.F., Armstrong, G.L., Farrington, L.A., Hutin, Y.J., Bell, B.P., 2006. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J. Hepatol. 45, 529-538.

Price, A.L., Patterson, N.J., Plenge, R.M., Weinblatt, M.E., Shadick, N.A., Reich, D., 2006. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904-909.

Pruim, R.J., Welch, R.P., Sanna, S., Teslovich, T.M., Chines, P.S., Gliedt, T.P., Boehnke, M., Abecasis, G.R., Willer, C.J., 2010. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336-2337.

Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Sklar, P., de Bakker, P.I., Daly, M.J., et al., 2007. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575.

Rawla, P., Sunkara, T., Muralidharan, P., Raj, J.P., 2018. Update in global trends and aetiology of hepatocellular carcinoma. Contemp. Oncol. (Pozn) 22, 141-150.

Robinson, P.C., Leo, P.J., Pointon, J.J., Harris, J., Cremin, K., Bradbury, L.A., Stebbings, S., Harrison, A.A., Duncan, E.L., Evans, D.M., et al., 2016. Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease. NPJ Genom. Med. 1, 16008.

Rumgay, H., Arnold, M., Ferlay, J., Lesi, O., Cabasag, C.J., Vignat, J., Laversanne, M., McGlynn, K.A., Soerjomataram, I., 2022. Global burden of primary liver cancer in 2020 and predictions to 2040. J. Hepatol. 77, 1598-1606.

Sawai, H., Nishida, N., Khor, S.S., Honda, M., Sugiyama, M., Baba, N., Yamada, K., Sawada, N., Tsugane, S., Koike, K., et al., 2018. Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma. Sci. Rep. 8, 7958.

Schaid, D.J., McDonnell, S.K., FitzGerald, L.M., DeRycke, L., Fogarty, Z., Giles, G.G., MacInnis, R.J., Southey, M.C., Nguyen-Dumont, T., Cancel-Tassin, G., et al., 2021. Two-stage study of familial prostate cancer by whole-exome sequencing and custom capture identifies 10 novel genes associated with the risk of prostate cancer. Eur. Urol. 79, 353-361.

Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., Bray, F., 2021. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209-249.

Wang, X., Menezes, C.J., Jia, Y., Xiao, Y., Venigalla, S.S.K., Cai, F., Hsieh, M.H., Gu, W., Du, L., Sudderth, J., et al., 2024. Metabolic inflexibility promotes mitochondrial health during liver regeneration. Science 384, eadj4301.

Wong, N., Lai, P., Pang, E., Leung, T.W., Lau, J.W., Johnson, P.J., 2000. A comprehensive karyotypic study on human hepatocellular carcinoma by spectral karyotyping. Hepatology 32, 1060-1068.

Xu, H.Z., Liu, Y.P., Guleng, B., Ren, J.L., 2014. Hepatitis B virus-related hepatocellular carcinoma: pathogenic mechanisms and novel therapeutic interventions. Gastrointest. Tumors 1, 135-145.

Yin, J., Zhang, H., He, Y., Xie, J., Liu, S., Chang, W., Tan, X., Gu, C., Lu, W., Wang, H., et al., 2010. Distribution and hepatocellular carcinoma-related viral properties of hepatitis B virus genotypes in Mainland China: a community-based study. Cancer epidemiology, biomarkers & prevention 19, 777-786.

Yu, R.B., Hong, X., Ding, W.L., Tan, Y.F., Zhang, Y.X., Sun, N.X., Wu, G.L., Zhan, S.W., Ge, D.F., 2008. The association between the genetic polymorphism of HLA-DQA1, DQB1, and DRB1 and serum alanine aminotransferase levels in chronic hepatitis C in the Chinese population. J. Gastroenterol. Hepatol. 23, 1394-1402.

Zois, C.E., Harris, A.L., 2016. Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy. J. Mol. Med. (Berl) 94, 137-154.

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