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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas
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Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas

机译：色素干色素性黑色素瘤中紫外线类型突变的证据

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摘要

To look for a direct role of ultraviolet radiation (UV) exposure in cutaneous melanoma induction, we studied xeroderma pigmentosum (XP) patients who have defective DNA repair resulting in a 1000-fold increase in melanoma risk. These XP melanomas have the same anatomic distribution as melanomas in the general population. We analyzed laser capture microdissection samples of skin melanomas from XP patients studied at the National Institutes of Health. The tumor suppressor gene PTEN was sequenced and analyzed for UV-induced mutations. Samples from 59 melanomas (47 melanomas in situ and 12 invasive melanomas) from 8 XP patients showed mutations in the PTEN tumor suppressor gene in 56% of the melanomas. Further, 91% of the melanomas with mutations had 1 to 4 UV type base substitution mutations (occurring at adjacent pyrimidines) (P < 0.0001 compared to random mutations). We found a high frequency of amino-acid-altering mutations in the melanomas and demonstrated that these mutations impaired PTEN function; UV damage plays a direct role in induction of mutations and in inactivation of the PTEN gene in XP melanomas including in situ, the earliest stage of melanoma. This gene is known to be a key regulator of carcinogenesis and therefore these data provide solid mechanistic support for UV protection for prevention of melanoma.
机译：为了寻找紫外线（UV）暴露在皮肤黑色素瘤诱导中的直接作用，我们研究了DNA修复缺陷导致黑色素瘤风险增加1000倍的色素干性皮肤病（XP）患者。这些XP黑色素瘤的解剖结构与普通人群中的黑色素瘤相同。我们分析了在国立卫生研究院研究的XP患者皮肤黑色素瘤的激光捕获显微切割样本。对肿瘤抑制基因PTEN进行测序，并分析紫外线诱导的突变。来自8位XP患者的59个黑色素瘤（47个原位黑色素瘤和12个浸润性黑色素瘤）的样本显示56％的黑色素瘤中PTEN抑癌基因发生突变。此外，具有突变的黑色素瘤中有91％具有1至4个UV型碱基取代突变（发生在相邻的嘧啶上）（与随机突变相比，P <0.0001）。我们在黑素瘤中发现了高频率的氨基酸改变突变，并证明这些突变损害了PTEN功能。紫外线损伤在XP黑素瘤（包括黑素瘤的最早阶段）包括原位的突变的诱导和PTEN基因的失活中起直接作用。已知该基因是致癌作用的关键调节剂，因此这些数据为预防黑素瘤的紫外线防护提供了坚实的机械支持。

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    Yun Wang; John J. DiGiovanna; Jere B. Stern; Thomas J. Hornyak; Mark Raffeld; Sikandar G. Khan; Kyu-Seon Oh; M. Christine Hollander; Philip A. Dennis; Kenneth H. Kraemer;

  • 作者单位

    Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 Division of Dermatopharmacology, Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, Rl 02912;

    Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Dermatology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

    Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    DNA repair; ultraviolet radiation; PTEN; skin cancer; laser capture microdissection;

    机译：DNA修复;紫外线辐射;PTEN;皮肤癌;激光捕获显微切割;

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