Nitric Oxide Synthase Polymorphisms and Risk for Skin Cancer

一氧化氮合酶多态性和皮肤癌风险

• 批准号: 7476508
• 负责人: Abrar A Qureshi
• 金额: $ 8.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476508
• 关键词: Adult; Affect; American Cancer Society; Amino Acids; Apoptosis; Arginine; Basal cell carcinoma; Biology; Burn injury; Categories; Cells; Cessation of life; Chemoprevention; Constitutional; Count; Cutaneous Melanoma; Cytostatics; Data; Diagnosis; Early Diagnosis; Endotoxins; Enzymes; Epidermis; Evaluation; Free Radicals; Future; Gases; Generations; Genes; Genetic Polymorphism; Genetic Variation; Hand; Haplotypes; Hospitals; Immunity; Individual; Inherited; Integration Host Factors; Interferon Type II; Laboratories; Langerhans cell; Life; Literature; Lung; Malignant Neoplasms; Mediating; Melanocytic nevus; Mole the mammal; Morbidity - disease rate; Nested Case-Control Study; Neurons; Nitric Oxide; Nitric Oxide Synthase; Numbers; Nurses' Health Study; Ovarian; Play; Population; Populations at Risk; Predisposition; Production; Recording of previous events; Rectal Cancer; Resources; Risk; Risk Factors; Role; Signaling Molecule; Skin; Skin Cancer; Skin Carcinoma; Specimen; Squamous cell carcinoma; Stratum Basale; Sun Exposure; Sunburn; Testing; Tissues; Topical agent; Ultraviolet Rays; United States; Variant; Vasodilation; Vasodilation disorder; Woman; Work; base; cancer cell; cancer risk; cell growth; chemotherapeutic agent; cohort; cytotoxic; interest; keratinocyte; melanocyte; melanoma; mortality; neuronal cell body; neurotransmission; skin cancer prevention; tumor growth; tumor progression

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.

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）和鳞状细胞癌（SCC）和恶性黑色素瘤。BCC和SCC与成人人群中的显著发病率相关。另一方面，在美国，黑素瘤与每年约7，910例死亡相关，并且美国癌症协会估计，仅在美国，2006年就将有62，190例新的黑素瘤病例。需要更好的策略来识别美国人群中有皮肤癌风险的个体，特别是如果早期诊断可以治愈的黑色素瘤。一氧化氮（NO）是一种气体，在身体的各种细胞中产生。这种气体由一组称为一氧化氮合酶（NOS）的酶从氨基酸L-精氨酸合成，即内皮型NOS（e）、诱导型NOS（i）和神经型NOS（n）。由于难以检测气态形式的短寿命NO，NOS酶的表达通常用作NO产生的替代物。在文献中有相当多的证据表明皮肤癌中NOS的表达是可变的。NO在介导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，NOS的差异表达与黑色素瘤的进展有关。有趣的是，NOS酶在SCC组织中高度表达，而它们在BCC标本中下调。迄今为止，皮肤癌的大部分工作都集中在癌症组织的体细胞变化上，以评估与癌症进展或死亡率的关联。该应用程序使用独特的资源，在一个嵌套的病例对照研究中，在Channing实验室，布里格姆和妇女医院的护士健康研究中，评估NOS基因变异可能与皮肤癌风险相关的假设。本申请的具体目的包括评估与黑素瘤、SCC和BCC风险相关的三种NOS基因的功能相关性和单倍型的多态性，并研究这些NOS变体与皮肤癌风险因素（晒伤次数、痣计数、晒黑能力和烧伤易感性）之间的关联。该应用的主要优势是在同一人群中同时评估SCC，BCC和黑色素瘤，其中大多数关于皮肤癌风险因素的数据是在诊断皮肤癌之前收集的。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增加或减少皮肤局部的产生来改变，因此可以根据这项工作的结果开发未来的化学预防策略。