Genome-wide association study of the TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and infection with hepatitis B virus

Abstract

Background: Exposure to dietary aflatoxin B1 (AFB1) induces DNA damage and mutation in the TP53 gene at codon 249, known as the TP53 R249S mutation, and is a major risk factor for hepatocellular carcinoma (HCC). AFB1 and the hepatitis B virus (HBV) together exert synergistic effects that promote carcinogenesis and TP53 R249S mutation in HCC.Methods: A genome-wide association study (GWAS) of whole genome exons was conducted using 485 HCC patients with chronic HBV infection. This was followed by an independent replication study conducted using 270 patients with chronic HBV infection. Immunohistochemistry was used to evaluate TP53 expression in all samples. This showed a correlation between codon 249 mutations and TP53 expression. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both the GWAS and replication study. The associations between identified variants and the expression levels of their located genes were analyzed in 20 paired independent samples. Results:The likelihood of positive TP53 expression was found to be higher in HCC patients with the R249S mutation both in the GWAS (P<0.001) and the replication study (P=0.006). The combined analyses showed that the TP53 R249S mutation was significantly associated with three single nucleotide polymorphisms (SNPs): ADAMTS18 rs9930984 (adjusted P=4.84×10 −6 ), WDR49 rs75218075 (adjusted P=7.36×10 −5 ), and SLC8A3 rs8022091 (adjusted P=0.042). The TP53 R249S mutation was found to be highly associated with the TT genotypes of rs9930984 (additive model, P=0.01; dominant model, P=6.43×10 −5

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“…Among more than 20 kinds of aflatoxin derivatives, AFB 1 possesses the highest toxicity of liver cancer and immune system damage. AFB 1 causes carcinogenesis in the presence of the double bond of AFB 1 furan ring by inhibiting RNA synthesis [ 4 ]. The lactone ring of AFB 1 is the main toxicity site.…”

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“…Furthermore, it participates in a family of genes that encode proteins regulating various cellular functions, such as cell division and cell fate determination, ontology-enriched pathways, transcription, transmembrane signaling, mRNA modification, and vesicle fusion [ 27 , 28 ]. However, in a GWAS study of patients with hepatocellular carcinoma and chronic hepatitis B virus (HBV) infection, Han et al (2020) reported low expression of WDR49 [ 29 ].…”

Loco-Regional Treatments for Hepatocellular Carcinoma in People Living with HIV

“…Other less common causes of cirrhosis contribute to a risk of developing HCC, including primary biliary cirrhosis, autoimmune hepatitis and hemochromatosis [ 29 , 30 , 31 , 32 ]. In some regions of Asia and Africa, exposure to aflatoxin B1, due to fungal contamination of staple foods, is related to the development of mutations (TP 53 codon 249, known as TP53 R249S) that lead to the development of HCC in patients with HBV infection [ 21 , 22 , 28 , 33 ].…”