RGD Reference Report - Trans-acting non-synonymous variant of FOXA1 predisposes to hepatocellular carcinoma through modulating FOXA1-ERα transcriptional program and may have undergone natural selection. - Rat Genome Database

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Trans-acting non-synonymous variant of FOXA1 predisposes to hepatocellular carcinoma through modulating FOXA1-ERα transcriptional program and may have undergone natural selection.

Authors: Wang, Sheng  Xiang, Chan  Mou, Lin  Yang, Yuan  Zhong, Rong  Wang, Liyan  Sun, Chang  Qin, Zhaoyu  Yang, Jingmin  Qian, Ji  Zhao, Yuanyuan  Wang, Yi  Pan, Xuedong  Qie, Jingbo  Jiang, Yan  Wang, Xiaofeng  Yang, Yajun  Zhou, Wei-Ping  Miao, Xiaoping  He, Fuchu  Jin, Li  Wang, Haijian 
Citation: Wang S, etal., Carcinogenesis. 2020 Apr 22;41(2):146-158. doi: 10.1093/carcin/bgz136.
RGD ID: 151665752
Pubmed: PMID:31400761   (View Abstract at PubMed)
DOI: DOI:10.1093/carcin/bgz136   (Journal Full-text)

Interplay of pioneer transcription factor forkhead box A1 (FOXA1) and estrogen receptor has been implicated in sexual dimorphism in hepatocellular carcinoma (HCC), but etiological relevance of its polymorphism was unknown. In the case control study (1152 patients versus1242 controls), we observed significant increase in HCC susceptibility in hepatitis B virus carriers associated with a non-synonymous Thr83Ala variant of FOXA1 (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.11-1.48, for Ala83-containing genotype, after validation in an independent population with 933 patients versus 1030 controls), a tightly linked (CGC)5/6or7 repeat polymorphism at its promoter (OR 1.32; 95% CI 1.10-1.60, for (CGC)6or7-repeat-containing genotype), and their combined haplotype (OR 1.50; 95% CI 1.24-1.81, for (CGC)6or7-Ala83 haplotype). The susceptible FOXA1-Ala83 impairs its interaction with ERα, attenuates transactivation toward some of their dual target genes, such as type 1 iodothyronine deiodinase, UDP glucuronosyltransferase 2 family, polypeptide B17 and sodium/taurocholate cotransporting polypeptide, but correlates with strengthened cellular expression of α-fetoprotein (AFP) and elevated AFP serum concentration in HCC patients (n = 1096). The susceptible FOXA1 cis-variant with (CGC)6or7 repeat strengthens the binding to transcription factor early growth response 1 and enhances promoter activity and gene expression. Evolutionary population genetics analyses with public datasets reveal significant population differentiation and unique haplotype structure of the derived protective FOXA1-Thr83 and suggest that it may have undergone positive natural selection in Chinese population. These findings epidemiologically highlight the functional significance of FOXA1-ERα transcriptional program and regulatory network in liver cancer development.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
FOXA1Humanhepatocellular carcinoma susceptibilityIAGP DNA:VNTR more ...RGD 
Foxa1Rathepatocellular carcinoma susceptibilityISOFOXA1 (Homo sapiens)DNA:VNTR more ...RGD 
Foxa1Mousehepatocellular carcinoma susceptibilityISOFOXA1 (Homo sapiens)DNA:VNTR more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Foxa1  (forkhead box A1)

Genes (Mus musculus)
Foxa1  (forkhead box A1)

Genes (Homo sapiens)
FOXA1  (forkhead box A1)


Additional Information