SUNLIGHT-RELATED STEPS IN HUMAN SKIN CANCER

逆转录病毒或单剂量烷化剂等试剂有 揭示了肿瘤发生的基本机制。然而，分子细节 致癌物和肿瘤之间的联系对任何人类来说都是未知的 癌症。在非黑色素瘤皮肤癌的情况下，这些信息包括 经常因阳光而突变的基因的同一性及其作用 不同的阳光波长导致了这些突变。 非黑色素瘤皮肤癌提供了一个机会，将阳光与其 遗传效应，因为直接吸收的紫外光留下了 突变特征有别于其他致癌物质。CC-&>TT转换 实际上是紫外线独有的；此外，大多数其他紫外线诱导的突变 是二嘧啶中心的C-&GT；T转变。这些突变将揭示 目标基因和它们的诱变剂。在我们的初步研究中，我们 在At中发现p53抑癌基因的CC-&GT；TT和C-GT；T突变 至少40%的人类皮肤鳞状细胞癌。 我们建议：1)用聚合酶链式反应检测P53基因 对于假定的前体病变中与阳光相关的突变，光化性 角化病；非转移性角质形成细胞瘤，基底细胞癌； 和一种黑素细胞瘤，有明确的阳光病因；恶性雀斑 黑色素瘤。色素性干皮病患者的肿瘤将被检查以 区分错误修复突变和错误复制突变。2)审查 同样，Fos基因以及H、K和N-RAS基因的调控区。 3)检查P53和视网膜母细胞瘤基因的等位基因丢失，这可能 是由阳光的长波紫外线成分引起的。 这些研究将有助于阐明阳光紫外线 与DNA相互作用，最终导致与阳光相关的癌症。会的 提供关于有效紫外线波长的信息，这些基因中 光被吸收，DNA光产物，突变的类型， 涉及的核苷酸和可能的热点序列。

Reagents such as retroviruses or single doses of alkylating agents have revealed basic mechanisms of oncogenesis. However, the molecular details of the link between carcinogen and tumor are not known for any human cancer. In the case of non-melanoma skin cancer, this information includes the identity of the genes frequently mutated by sunlight and the role of various sunlight wavelengths in causing these mutations. Non-melanoma skin cancers provide an opportunity to link sunlight to its genetic effect, because directly-absorbed ultraviolet light leaves a mutational signature distinct from other carcinogens. CC -> TT transitions are virtually unique to UV; in addition, most other UV-induced mutations are C -> T transitions at dipyrimidine sites. These mutations would reveal both the target genes and their mutagen. In our preliminary studies, we found CC-> TT and C -> T mutations in the p53 tumor suppressor gene in at least 40% of human squamous cell carcinomas of skin. We propose to: 1) Use the polymerase chain reaction to examine the p53 gene for sunlight-related mutations in a putative precursor lesion, actinic keratosis; a non-metastasizing keratinocyte tumor, basal cell carcinoma; and a melanocyte tumor with a clear sunlight etiology; lentigo maligna melanoma. Tumors from xeroderma pigmentosum patients will be examined to distinguish misrepair mutations from misreplication mutations. 2) Examine similarly the FOS gene and regulatory regions of the H, K, and N RAS genes. 3) Examine the p53 and retinoblastoma genes for loss of alleles, which can be caused by long-wavelength UV components of sunlight. These studies will help elucidate the mechanisms by which sunlight UV interacts with DNA to eventually lead to sunlight-related cancers. It will provide information on the effective UV wavelengths, the genes in which the light is absorbed, the DNA photoproducts, the types of mutations, the nucleotides involved, and possible hotspot sequences.