PubMed · 9071995
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P D Barrett, A J Malcolm. 1997. Molecular abnormalities in liposarcoma.. https://doi.org/10.1002/(sici)1096-9896(199701)181%3A1%3C3%3A%3Aaid-path817%3E3.0.co%3B2-g
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The tumor suppressor protein p53 plays a critical role in the orchestration of the cellular responses to a variety of genotoxic and cytotoxic stresses. Mutations or functional inactivation of p53 seriously compromise these cellular processes and foster tumor development. p53 is the most frequently mutated gene in human cancers and over 90% of human non-melanoma skin cancers (NMSC) harbour p53 mutation. It plays a vital role in the control of the immediate and adaptive responses to ultraviolet radiation (UV) and the onset of NMSC. During the process of photocarcinogenesis, UV-specific p53 mutations occur early in the keratinocytes resulting in the loss of the wild type p53 function and continued UV exposure leads to clonal expansion of p53-mutated keratinocytes and promotion of skin tumors. Precisely how clones of keratinocytes containing such mutations, in an apparently normal epidermis, progress to a malignant carcinoma is unknown. Further examination of the functional significance of these UV-p53 mutations in affecting the immediate and adaptive responses of the skin to UV is critical to the development of effective prevention and therapeutic strategies for human skin cancer. The purpose of this article is to provide an overview of accumulating evidence pointing towards a critical role for p53 mutation in photocarcinogenesis.
Myelodysplastic syndrome (MDS) consists of a heterogeneous group of acquired hematopoietic stem cell disorders, characterized by bone marrow failure and leukemic transformation. Since hematological manifestations and clinical outcomes vary widely among MDS patients, a considerable number of studies have tried to identify the prognostic parameters for the stratification of patients into different risk groups. Based on reported risk-based studies, the International Prognostic Scoring System (IPSS) was proposed as a reliable risk assessment method for primary MDS patients, and several validating studies have clarified its usefulness. Critical prognostic parameters of the IPSS consist of chromosome findings, the percentage of marrow blasts, and the number of peripheral blood cytopenias. Although other laboratory findings, including several molecular alterations, have been identified as convincing prognostic factors in MDS, these molecular configurations were not selected as prognostic parameters in the IPSS, because analysis for these alterations were not routinely available for the management of patients with MDS. Because recent advances in molecular genetics may make it available as a routine work-up of MDS in the future, we discuss potential improvement of the IPSS by the addition of molecular analysis to the system, with particular reference to the configuration of the TP53 gene.
Genomic instability is a hallmark of cancer cells, and is thought to be involved in the process of carcinogenesis. Indeed, a number of rare genetic disorders associated with a predisposition to cancer are characterised by genomic instability occurring in somatic cells. Of particular interest is the observation that transmissible instability can be induced in somatic cells from normal individuals by exposure to ionising radiation, leading to a persistent enhancement in the rate at which mutations and chromosomal aberrations arise in the progeny of the irradiated cells after many generations of replication. If such induced instability is involved in radiation carcinogenesis, it would imply that the initial carcinogenic event may not be a rare mutation occurring in a specific gene or set of genes. Rather, radiation may induce a process of instability in many cells in a population, enhancing the rate at which the multiple gene mutations necessary for the development of cancer may arise in a given cell lineage. Furthermore, radiation could act at any stage in the development of cancer by facilitating the accumulation of the remaining genetic events required to produce a fully malignant tumour. The experimental evidence for such induced instability is reviewed.