Does radiation cause molecular signatures?

Conference · Sat Mar 01 04:00:00 EST 1997

OSTI ID:526028

Bennett, W P ^[1]

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1. National Cancer Institute, Bethesda, MD (United States)

Several classes of genes are mutated during the progression to cancer. The oncogenes include ras, myc and c-erbB-2; suppressor genes include p53, Rb, p16, and APC; and cancer susceptibility genes include hMSH2. Germline mutations in many of these genes produce cancer syndromes such as retinoblastoma, Li-Fraumeni Sydrome, familial adenomatous polyposis, or HNPCC (hereditary non-polyposis colon cancer). Sporadic tumors frequently contain somatic mutations in the same genes. Analysis of the mutational spectrum of sporadic and inherited tumors can provide clues to etiology and insight into molecular pathogenesis. The character and distribution of mutations comprise a mutational spectrum. Mutations of the p53 tumor suppressor gene occur commonly in human cancer, and nearly 5000 have been reported to date. The p53 mutational spectrum is dominated by missense point mutations (84%) and complemented by insertions/deletions (10%) and non-sense mutations (7%). Most mutations occur within evolutionarily conserved residues within the DNA-binding domain, and the pattern of mutational hotspots provided the first clue to p53 function: it is a transcription factor that binds to a DNA consensus sequence. Elucidation of the crystal structure of the central DNA-binding domain has uncovered the significance of the mutational hotspots. These insights suggest strategies for rational drug design, for example, constructing `restoring` compounds that complete the wild type hydrogen bonds missing in the mutant p53 protein. Mutational spectrum analysis is a new tool for probing cancer etiology and pathogensis. Using current technology, the p53 tumor suppressor gene is the most informative target sequence, but the next generation of rapid sequencing technologies will expand the range of testable cancer genes and fill new mutational databases.

• Research Organization: National Council on Radiation Protection and Measurements, Bethesda, MD (United States)
• OSTI ID: 526028
• Report Number(s): CONF-960405--
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
BIOLOGICAL RADIATION EFFECTS
CARCINOGENESIS
GENES
GENETICS
MOLECULAR STRUCTURE
ONCOGENES