The p53 tumor suppressor gene has come to the forefront of cancer research because it is commonly mutated in human cancer and the spectrum of p53 mutations in these cancers is providing clues to the etiology and molecular pathogenesis of neoplasia (1â€”3). Detection of p53 abnormalities may have diagnostic, prognostic, and therapeutic implications (4). The 15-year history of p53 investigations is a paradigm in cancer research, illustrating the convergence of previously parallel lines of basic, clinical, and epidemiological investigation and the rapid trans fer of research findings from the laboratory to the clinic. p53 is clearly a component in biochemical pathways central to human carcinogen esis; p53 protein alterations due to missense mutations and loss of p53 protein by nonsense or frameshift mutations provide a selective ad vantage for clonal expansion of preneoplastic and neoplastic cells (5). The potential for a missense mutation to cause loss of tumor suppres sor function and gain of oncogenic activity, i.e., to transform cells by two mechanisms, is one explanation for the commonality of p53 mutations in human cancer. Recent studies investigating the mecha nisms underlying the biological activity of p53 indicate that the protein is involved in gene transcription, DNA synthesis and repair, genomic plasticity, and programmed cell death (1â€”6).These complex biochemical processes are performed by multicomponent protein ma chines; therefore, it is not surprising that the p53 protein forms complexes with other cellular proteins (Fig. 1) and that some viral oncoproteins alter the functions of these machines by binding to p53 and perturbing its interaction with other cellular protein components. In this Perspective, we will focus on the origin of p.53 mutations, the mutational spectrum of p.53 in human cancers, and the hypotheses generated by the analysis of p53 mutations in premalignant and malignant cells. The interpretation ofp53 mutations in human cancers is based on observations of the patterns of DNA damage induced by chemical and physical mutagens in model systems. In this Introduc tion, we will review these data, which provide the background for many of the inferences drawn from p53 mutational analysis.

https://cancerres.aacrjournals.org/content/canres/54/18/4855.full.pdf

Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesis

Cancer burden in the year 2000. The global picture.

Hepatocellular carcinoma is among the most lethal and prevalent cancers in the human population. Despite its significance, there is only an elemental understanding of the molecular, cellular and environmental mechanisms that drive disease pathogenesis, and there are only limited therapeutic options, many with negligible clinical benefit. This Review summarizes the current state of knowledge of this, the most common and dreaded liver neoplasm, and highlights the principal challenges and scientific opportunities that are relevant to controlling this accelerating global health crisis.

/pdf/hepatocellular-carcinoma-pathogenesis-from-genes-to-lr3tx2lfl6.pdf

Hepatocellular carcinoma pathogenesis: from genes to environment

Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.

Radical causes of cancer

Hepatocarcinogenesis is a slow process during which genomic changes progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into hepatocellular carcinoma. During the long preneoplastic stage, in which the liver is often the site of chronic hepatitis, cirrhosis, or both, hepatocyte cycling is accelerated by upregulation of mitogenic pathways, in part through epigenetic mechanisms. This leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomere erosion and telomerase re-expression, sometimes microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and emergence of hepatocellular carcinoma are associated with the accumulation of irreversible structural alterations in genes and chromosomes, but the genomic basis of the malignant phenotype is heterogeneous. The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma. New strategies should enable these variants to be characterized.

Molecular pathogenesis of human hepatocellular carcinoma

Fifty-eight percent of hepatocellular carcinomas (HCCs) from Qidong, China, contain an AGG to AGT mutation at codon 249 of the p53 tumor suppressor gene, a mutation that is rarely seen in HCCs from Western countries. The population of Qidong is exposed to high levels of aflatoxin B1 (AFB1), a fungal toxin that has been shown to induce the same mutation in cultured human HCC cells. To investigate the role of AFB1 and of these p53 mutations in hepatocarcinogenesis, normal liver samples from the United States, Thailand, and Qidong (where AFB1 exposures are negligible, low and high, respectively) were examined for p53 mutations. The frequency of the AGG to AGT mutation at codon 249 paralleled the level of AFB1 exposure, which supports the hypothesis that this toxin has a causative--and probably early--role in hepatocarcinogenesis.

https://science.sciencemag.org/content/sci/264/5163/1317.full.pdf

F Aguilar

Papers

Geographic Variation of p53 Mutational Profile in Nonmalignant Human Liver