DNA Repair in Human Cancer-Prone Genetic Diseases

人类易患癌症的遗传疾病中的 DNA 修复

• 批准号: 7337789
• 负责人: KENNETH H KRAEMER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7337789
• 关键词: DNA; Repair; Human; Cancer; Prone

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.

该实验室正在研究易人癌症遗传疾病的分子，细胞和临床异常。目前的研究集中在易胚层色素（XP）一种容易产生癌症的遗传疾病，对环境药物的细胞超敏反应和毛胸部疾病（TTD）是一种遗传疾病，具有相似的细胞超敏反应，但癌症风险没有增加。我们确定了几个不寻常的XP患者。我们发现，根据产生的正常XPC mRNA的量，XPC基因的剪接延本分支点序列的突变会导致严重或轻度的临床症状。我们发现，XPC患者的正常出现父母显着降低了XPC mRNA的水平。我们确定了XPB解旋酶中突变的新患者，XPB解旋酶是一种对生命必不可少的蛋白质，参与转录和DNA修复。这些患者因其突变而患有严重或轻度疾病。在一项合作研究中，我们发现XPA创始人突变的频率接近日本一般人群的1％。我们已经开始了一项协作分子流行病学研究，以检查XP DNA修复基因突变携带者的癌症风险。发现XP的皮肤癌与口服13-CIS视黄酸的皮肤癌被发现有效防止皮肤癌，但非常有毒。不同患者的有效剂量最低剂量有所不同。