Z01 BC 004517 (Z01) | |||
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Title | DNA Repair in Human Cancer-Prone Genetic Diseases | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Kraemer, Kenneth | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $864,697 | Project Dates | 10/01/1977 - N/A |
Fiscal Year | 2007 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Aging (15.0%) Chemoprevention (30.0%) Childhood Cancers (50.0%) Genetic Testing (50.0%) Neurosciences Research (10.0%) |
Brain (10.0%) Eye (25.0%) Melanoma (30.0%) Nervous System (10.0%) |
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Research Type | |||
Cancer Initiation: Alterations in Chromosomes Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
The laboratory is studying molecular, cellular and clinical abnormalities in human cancer-prone genetic diseases. Current studies are focusing on xeroderma pigmentosum (XP) a cancer-prone genetic disease with cellular hypersensitivity to environmental agents and trichothiodystrophy (TTD) a genetic disease with similar cellular hypersensitivity but no increase in cancer risk. We identified several unusual XP patients. We found that mutations in the splice lariat branch point sequence of the XPC gene result in either severe or mild clinical symptoms depending on the amount of normal XPC mRNA produced. We found that normal appearing parents of XPC patients have markedly reduced levels of XPC mRNA. We identified new patients with mutations in the XPB helicase, a protein that is essential for life and is involved in transcription and DNA repair. These patients had severe or mild disease depending on their mutations. In a collaborative study we found that the frequency of an XPA founder mutation approaches 1% of the general population in Japan. We have begun a collaborative molecular epidemiology study to examine the cancer risk in carriers of mutations in XP DNA repair genes. Chemoprevention of skin cancer in XP with oral 13-cis retinoic acid was found to be effective in preventing skin cancers but very toxic. The lowest effective dose varied in different patients. |