DNA Repair in Human Cancer-Prone Genetic Diseases

人类易患癌症的遗传疾病中的 DNA 修复

基本信息

项目摘要

We completed a follow-up report on all 106 XP patients we examined at the NIH Clinical Center since 1971. There was a 10000-fold increase in non-melanoma skin cancer (NMSC) and a 2000-fold increase in melanoma skin cancer in XP patients under age 20. The 9 year median age of diagnosis of first NMSC was significantly younger than the 22 year median age of melanoma - a relative reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. The median age at death of XP patients with neurodegeneration (29 years) was significantly younger than XP patients without neurodegeneration (37 years). This 39 year study indicates a major role for DNA repair genes in the etiology of skin cancer and neurodegeneration. We analyzed hearing function of all XP patients admitted to NIH from 1971 to 2012. We found that audiograms can serve as predictors of patients that will develop progressive neurological degeneration. In collaboration with ophalmologists of the NEI we published a summary of the eye abnormalities in the XP patients examined at the NIH from 1964 to 2011. This highlights the role of DNA repair in protection from sun damage. We have established several hundred carefully documented cell lines and contributed them to cell banks for use of the general scientific community. Our laboratory has become a major center in the US for basic, clinical and translational expertise concerning DNA repair related disorders. We have now identified mutations in all 8 DNA nucleotide excision repair (NER) genes (XPA, XPB, XPC, XPD, XPE, XPF, XPG, and TTDA) and in the error-prone polymerase, pol eta in more than 150 XP and TTD families. In a study of 16 XP-C families we found that most of the XP-C patients had mutations leading to premature stop codons. We found low levels of XPC mRNA in XPC patients while their obligate heterozygote parents had an intermediate level of XPC mRNA between the patients and the normal controls. We found two XP-C families from Turkey that had severe or mild disease that correlated with mutations in two different splice lariat branchpoints (LBP). These LBP mutations resulted in no measurable XPC mRNA or a low (3%) level of XPC mRNA, respectively. This indicates that a) low levels of normal XPC mRNA may provide some protection against cancer and b) reduced levels may increase cancer risk (e.g. potential risk to heterozygotes).We found a wide spectrum of mutations in pol eta in cells from 10 XP variant families in America, Europe and Asia. We are continuing to compare the genotype to the clinical features of XP patients and to characterize the progressive neurologic degeneration that occurs in some XP patients because it may be a model for more common neurodegenerative disorders. In contrast to the profound environmental influence on XP, TTD is a disease of altered development. We performed a comprehensive literature review and identified reports of 112 TTD cases. We found a wide variety of clinical symptoms in many organ systems including an unsuspected 20-fold increase in mortality in children under age 10 years primarily due to infections. We documented significant increased frequency of complications in pregnancies of TTD affected fetuses compared to pregnancies carrying their unaffected siblings and to the general population. More than 80% of these pregnancies had one or more complications. The TTD affected neonates had high frequency of abnormalities including low birth weight, cataracts and cryptorchidism. This date provides evidence of DNA repair gene function in human fetal growth and pregnancy possibly by altering the development of the placenta. We found that these severe pregnancy and prenatal development complications were present only in mothers with TTD affected children, and not with their unaffected children or in mothers with XP affected children. This is an important finding since the TTD affected children and the XP affected children have different mutations in the same gene (XPD) which is involved in both DNA repair and transcription. Using localized UV irradiation we were able to show a consistent difference in the pattern of movement of NER proteins in cultured cells from XP or TTD patients with different XPD defects. In XP cells at late times after UV, the NER proteins persisted at sites of unrepaired DNA damage. In contrast, in TTD cells the NER proteins did not persist. These differences suggest a mechanism that may explain the difference between the increased cancer susceptibility in XP patients and the absence of increased cancer in TTD. There was a similar persistence of NER proteins at sites of DNA damage in cells with defects in the XPC, XPB and DDB2/XPE genes. While skin cancer is the most common cancer occurring in the US, and rates of melanoma, the most dangerous skin cancer are rapidly increasing, there remains controversy as to the role of UV in induction of cutaneous melanomas. Because of their high frequency of melanomas, XP patients are a unique resource to study the pathophysiology of melanoma. We used laser capture micro-dissection to remove melanoma cells from tissue blocks of XP melanomas and sequenced the PTEN tumor suppressor gene. We found a high frequency of UV-type mutations in 59 XP melanomas. These data provide evidence for a direct effect of UV in the development of melanoma. We determined that a unique patient with melanoma, deafness and DNA repair deficiency had a translocation between chromosomes 9 and 22. His cells had a break in the p14arf tumor suppressor gene on chr 9 leading to reduced DNA repair and melanoma. Expression of TBX1, a gene on chr 22 that is important in ear development was reduced in his cells. The translocation produced a chimeric mRNA that served as a dominant negative regulator of p14arf and TBX1. This provides important insights into the causes of melanoma and regulation of inner ear development.
我们完成了自 1971 年以来在 NIH 临床中心检查的所有 106 名 XP 患者的随访报告。XP 中非黑色素瘤皮肤癌 (NMSC) 增加了 10000 倍,黑色素瘤皮肤癌增加了 2000 倍20 岁以下的患者。首次 NMSC 诊断的中位年龄为 9 岁,明显低于黑色素瘤的中位年龄 22 岁——与一般人群的相对逆转提示 NMSC 和黑色素瘤之间不同的致癌机制。患有神经退行性变的 XP 患者的中位死亡年龄(29 岁)明显低于没有神经退行性病变的 XP 患者(37 岁)。这项历时 39 年的研究表明 DNA 修复基因在皮肤癌和神经退行性疾病的病因学中发挥着重要作用。我们分析了 1971 年至 2012 年 NIH 收治的所有 XP 患者的听力功能。我们发现听力图可以作为患者发生进行性神经退行性变的预测指标。我们与 NEI 的眼科医生合作,发表了 1964 年至 2011 年在 NIH 检查的 XP 患者眼部异常的摘要。这强调了 DNA 修复在防止阳光损伤中的作用。我们已经建立了数百个经过仔细记录的细胞系,并将它们贡献给细胞库以供一般科学界使用。我们的实验室已成为美国有关 DNA 修复相关疾病的基础、临床和转化专业知识的主要中心。我们现已鉴定出所有 8 个 DNA 核苷酸切除修复 (NER) 基因(XPA、XPB、XPC、XPD、XPE、XPF、XPG 和 TTDA)以及 150 多个 XP 和易错聚合酶 pol eta 中的突变。 TTD 家庭。在一项针对 16 个 XP-C 家族的研究中,我们发现大多数 XP-C 患者都有导致提前终止密码子的突变。我们发现 XPC 患者的 XPC mRNA 水平较低,而其专性杂合子父母的 XPC mRNA 水平介于患者和正常对照之间。我们发现来自土耳其的两个 XP-C 家族患有严重或轻度疾病,这些疾病与两个不同剪接套索分支点 (LBP) 的突变相关。这些 LBP 突变分别导致无法测量 XPC mRNA 或 XPC mRNA 水平较低 (3%)。这表明 a) 低水平的正常 XPC mRNA 可能提供一定的抗癌保护作用,b) 水平降低可能会增加癌症风险(例如杂合子的潜在风险)。我们在 10 XP 变体的细胞中发现了广泛的 pol eta 突变美洲、欧洲和亚洲的家庭。我们正在继续将基因型与 XP 患者的临床特征进行比较,并描述一些 XP 患者中发生的进行性神经退行性变的特征,因为它可能是更常见的神经退行性疾病的模型。与环境对 XP 的深远影响相反,TTD 是一种发育改变的疾病。我们进行了全面的文献回顾并确定了 112 个 TTD 病例的报告。我们在许多器官系统中发现了各种各样的临床症状,其中包括 10 岁以下儿童的死亡率意外增加了 20 倍,这主要是由于感染所致。我们记录了与未受影响的兄弟姐妹和一般人群相比,受 TTD 影响的胎儿怀孕时并发症的发生率显着增加。超过 80% 的妊娠出现一种或多种并发症。受 TTD 影响的新生儿出现异常的频率很高,包括低出生体重、白内障和隐睾。这一日期提供了 DNA 修复基因在人类胎儿生长和妊娠中可能通过改变胎盘发育发挥功能的证据。我们发现,这些严重的妊娠和产前发育并发症仅存在于患有 TTD 影响儿童的母亲中,而不存在于未受影响的孩子或患有 XP 影响儿童的母亲中。这是一个重要的发现,因为受 TTD 影响的儿童和受 XP 影响的儿童在参与 DNA 修复和转录的同一基因 (XPD) 中存在不同的突变。使用局部紫外线照射,我们能够显示来自具有不同 XPD 缺陷的 XP 或 TTD 患者的培养细胞中 NER 蛋白运动模式的一致差异。在 UV 后后期的 XP 细胞中,NER 蛋白持续存在于未修复的 DNA 损伤部位。相反,在 TTD 细胞中,NER 蛋白没有持续存在。这些差异表明了一种机制,可以解释 XP 患者癌症易感性增加与 TTD 患者癌症易感性不增加之间的差异。在 XPC、XPB 和 DDB2/XPE 基因缺陷的细胞中,DNA 损伤位点上的 NER 蛋白也有类似的持久性。虽然皮肤癌是美国最常见的癌症,而且最危险的皮肤癌黑色素瘤的发病率正在迅速增加,但关于紫外线在诱发皮肤黑色素瘤中的作用仍然存在争议。由于黑色素瘤发病率较高,XP 患者是研究黑色素瘤病理生理学的独特资源。我们使用激光捕获显微切割技术从 XP 黑色素瘤组织块中去除黑色素瘤细胞,并对 PTEN 肿瘤抑制基因进行测序。我们在 59 个 XP 黑色素瘤中发现了高频率的 UV 型突变。这些数据提供了紫外线对黑色素瘤发展的直接影响的证据。我们确定,一名患有黑色素瘤、耳聋和 DNA 修复缺陷的独特患者在 9 号和 22 号染色体之间发生了易位。他的细胞中第 9 号染色体上的 p14arf 肿瘤抑制基因发生了断裂,导致 DNA 修复减少并导致黑色素瘤。他的细胞中 TBX1 的表达减少了,TBX1 是第 22 号基因上的一个基因,对耳朵发育很重要。该易位产生了嵌合 mRNA,作为 p14arf 和 TBX1 的显性负调节因子。这为了解黑色素瘤的原因和内耳发育的调节提供了重要的见解。

项目成果

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KENNETH H KRAEMER其他文献

KENNETH H KRAEMER的其他文献

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{{ truncateString('KENNETH H KRAEMER', 18)}}的其他基金

DNA Repair in Human Cancer Prone Genetic Diseases
人类易患癌症的遗传病中的 DNA 修复
  • 批准号:
    6558867
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    10262007
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    7038117
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    6432993
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    8937627
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    8552563
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    7283967
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    6761422
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:
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:
    7592509
  • 财政年份:
  • 资助金额:
    $ 141.26万
  • 项目类别:

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