Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa

Abstract

Hepatocellular carcinoma (HCC) is a prevalent cancer in sub-Saharan Africa and eastern Asia. Hepatitis B virus and aflatoxins are risk factors for HCC, but the molecular mechanism of human hepatocellular carcinogenesis is largely unknown. Abnormalities in the structure and expression of the tumour-suppressor gene p53 are frequent in HCC cell lines, and allelic losses from chromosome 17p have been found in HCCs from China and Japan. Here we report on allelic deletions from chromosome 17p and mutations of the p53 gene found in 50% of primary HCCs from southern Africa. Four of five mutations detected were G----T substitutions, with clustering at codon 249. This mutation specificity could reflect exposure to a specific carcinogen, one candidate being aflatoxin B1 (ref. 7), a food contaminant in Africa, which is both a mutagen that induces G to T substitution and a liver-specific carcinogen.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…The ®rst correlation between a speci®c carcinogen and p53 was suggested by Harris, Ozturk and their colleagues (Hsu et al, 1991;Bressac et al, 1991) who identi®ed with a high frequency the presence of G4T transversion at codon 249 (R4S) in hepatocellular carcinomas (HCC) from southern Africa and eastern Asia (Bressac et al, 1991). Another example was provided by Brash et al studying the involvement of p53 in human squamous cell carcinomas (Brash et al, 1991).…”

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

“…Present data suggest a frequent involvement of p53 mutations (Bressac et al, 1991;Hsu et al, 1991) as well as functional RB-1 deletions in human HCCs (Nishida et al, 1992;Murakami et al, 1991;Walker et al, 1991). Furthermore, evidence for a tumour suppressor function of the insulin-like growth factor (IGF)-II receptor in liver tumourigenesis has accumulated (Yamada et al, 1997).…”

“…Thus macrodeletions were not found to encompass the p53 locus at 17p13.1, in consistence with the fact that frequently the loss of p53 function in HCCs is due to point mutations at codon 249 (Fujimoto et al, 1994;Bressac et al, 1991), and not to deletions as described for glioblastomas (Albertoni et al, 1998). Furthermore no significant gains of genomic material have been found at chromosomal locations of growth factors that are frequently overexpressed in HCCs, such as IGF-II (11p15.5) and TGFα (2p13), suggesting that genomic amplification is a rather unlikely cause of growth factor overexpression in HCCs.…”

Risk Factors for Hepatocellular Carcinoma in India

“…70 Carcinogenic activity of aflatoxin is attributed to covalent adduct formation by metabolically activated reactive intermediates with hepatocyte DNA, which could lead to mutations in the host genome. 71 Mutations of the p53 gene on chromosome 17 have been frequently found in primary liver cancer. [72][73][74] This hotspot mutation was originally described in HCC from regions with high levels of dietary aflatoxins, and is considered a hallmark of AFB1.…”