Nitric Oxide Synthase Polymorphisms and Risk for Skin Cancer

描述(由申请人提供)： 皮肤癌是美国最常见的皮肤癌类型。皮肤癌有两大类，非黑色素瘤类型，包括基底细胞癌(BCC)、鳞状细胞癌(SCC)和恶性黑色素瘤。基底细胞癌和鳞癌在成人人群中具有显著的发病率。另一方面，在美国，黑色素瘤每年与大约7910例死亡有关，美国癌症协会估计，仅在美国，2006年就会有62,190例新的黑色素瘤病例。需要更好的策略来识别美国人群中皮肤癌的风险个体，特别是黑色素瘤，如果及早诊断，黑色素瘤是可以治愈的。一氧化氮(NO)是一种在人体各种细胞中产生的气体。这种气体是由氨基酸L-精氨酸通过一组称为一氧化氮合酶的酶合成的，即内皮(E)、诱导型(I)和神经元型(N)一氧化氮合酶。由于检测气态短命NO的难度较大，NOS酶的表达通常被用来替代NO的产生。文献中有相当多的证据表明，皮肤癌中存在一氧化氮合酶的可变表达。一氧化氮在调节紫外线辐射对皮肤的影响方面也很重要，例如在阳光照射下。此外，一氧化氮合酶的差异表达与黑色素瘤的进展有关。有趣的是，一氧化氮合酶在鳞状细胞癌组织中高度表达，而在基底细胞癌组织中表达下调。到目前为止，皮肤癌方面的大部分工作都集中在癌症组织的躯体变化上，以评估与癌症进展或死亡率的关系。该应用程序使用钱宁实验室、布里格姆和妇女医院的护士健康研究中嵌套的病例对照研究中的独特资源来评估一氧化氮合酶基因变异可能与皮肤癌风险相关的假设。这项应用的具体目的包括评估三个一氧化氮合酶基因的多态与功能相关性和单倍型与黑色素瘤、鳞癌和基底细胞癌风险的关系，并调查这些一氧化氮合酶变异与皮肤癌风险因素(晒伤次数、摩尔计数、晒黑能力和烧伤敏感性)之间的关联。这一应用的一个主要优点是同时评估同一人群中的鳞癌、基底细胞癌和黑色素瘤，其中关于皮肤癌风险因素的大部分数据是在皮肤癌诊断之前收集的。最重要的是，由于一氧化氮的产生可以通过使用局部药物来改变，以增加或减少皮肤局部的产生，因此可以根据这项工作的结果制定未来的化学预防策略。

DESCRIPTION (provided by applicant): Skin cancer is the most common type of skin cancer in the United States. There are two broad categories of skin cancer, non-melanoma type that include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) and malignant melanoma. BCC and SCC are associated with significant morbidity amongst adult populations. On the other hand, melanoma is associated with about 7,910 deaths per year in the United States and the American Cancer Society estimates that there will be 62,190 new cases of melanoma in 2006 in the US alone. Better strategies are needed to identify individuals in the US population at risk for skin cancer, in particular melanoma which can be curable if diagnosed early. Nitric oxide (NO) is a gas that is produced in various cells of the body. This gas is synthesized from an amino acid L-arginine by a group of enzymes called nitric oxide synthases (NOS), i.e. endothelial (e), inducible (i), and neuronal (n)NOS. Because of the difficulty in detecting short-lived NO in gaseous form, expression of the NOS enzymes is commonly used as a surrogate for NO production. There is considerable evidence in the literature to implicate variable expression of NOS in skin cancer. NO is also important in mediating the effects of ultraviolet radiation on the skin such as with sun exposure. Also, differential expression of NOS has been associated with progression of melanoma. Interestingly, NOS enzymes are highly expressed in SCC tissue whereas they are down-regulated in BCC specimens. Most of the work in skin cancer thus far has focused on somatic changes in cancer tissue to evaluate the association with cancer progression or mortality. This application uses unique resources in a nested case-control study within the well-characterized Nurses' Health Study at the Channing Laboratory, Brigham and Women's Hospital to evaluate the hypothesis that NOS gene variants may be associated with a risk for skin cancer. This specific aims of this application include evaluation of polymorphisms with functional relevance and haplotypes of the three NOS genes in relation to risk for melanoma, SCC and BCC and to investigate associations between these NOS variants and risk factors for skin cancer (number of sunburns, mole counts, ability-to-tan and susceptibility-to-burn). A major strength of this application is the simultaneous evaluation of SCC, BCC and melanoma in the same population-based cohort of women where majority of the data on skin cancer risk factors was collected prior to the diagnosis of skin cancer. Most important, as nitric oxide production can be modified by using topical agents to increase or decrease production locally in the skin, future chemoprevention strategies may be developed based on results of this work.