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.

该实验室正在研究人类易患癌症的遗传疾病的分子、细胞和临床异常。目前的研究重点是色素性干皮病 (XP) 和毛发硫营养不良 (TTD)，前者是一种易患癌症的遗传性疾病，细胞对环境因素过敏，而毛发硫营养不良 (TTD) 是一种具有类似细胞过敏性但不增加癌症风险的遗传性疾病。我们发现了几位不寻常的 XP 患者。我们发现 XPC 基因剪接套索分支点序列的突变会导致严重或轻微的临床症状，具体取决于产生的正常 XPC mRNA 的量。我们发现 XPC 患者的正常父母的 XPC mRNA 水平显着降低。我们发现了 XPB 解旋酶发生突变的新患者，XPB 解旋酶是一种生命必需的蛋白质，参与转录和 DNA 修复。这些患者患有严重或轻微的疾病，具体取决于他们的突变。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总人口的 1%。我们已经开始一项合作性分子流行病学研究，以检查 XP DNA 修复基因突变携带者的癌症风险。口服 13-顺式视黄酸对 XP 皮肤癌进行化学预防被发现可有效预防皮肤癌，但毒性很大。不同患者的最低有效剂量有所不同。