Molecular Calssification of Basal Cell Carcinomas

基底细胞癌的分子分类

• 批准号: 6795058
• 负责人: Allen Everett Bale
• 金额: $ 16.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-26 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6795058
• 关键词: autoradiography; basal cell carcinoma; blood chemistry; clinical research; computer assisted sequence analysis; gene expression; gene mutation; genetic polymorphism; human genetic material tag; in situ hybridization; metastasis; microarray technology; molecular oncology; molecular pathology; neoplasm /cancer classification /staging; neoplasm /cancer genetics; nucleic acid sequence; oncogenes; polymerase chain reaction; single nucleotide polymorphism; southern blotting

DESCRIPTION (provided by applicant): Basal cell carcinoma of the skin is by far the most common type of cancer in the United States, representing nearly one half of all newly diagnosed malignancies. Although these tumors infrequently cause cancer mortality, they are associated with significant morbidity due to local invasion and tissue destruction. Basal cell carcinomas are extremely variable in gross and microscopic appearance and biological behavior, and a common histopathologic classification system divides the tumors into five main categories which differ in aggressiveness, prognosis, and response to therapy. My laboratory isolated a gene for hereditary basal cell carcinomas (human patched; gene symbol PTCH) and showed that this gene is mutated in sporadic BCCs as well. Exactly analogous to the two-hit paradigm established for retinoblastoma, almost all sporadic basal cell tumors have two somatically-derived, inactivating PTCH mutations. PTCH is a member of the hedgehog signal transduction pathway. The few BCCs lacking mutations in PTCH have activating mutations in smoothened (SMO), another member of the hedgehog pathway whose protein is normally repressed by the patched protein. All subtypes of BCCs have mutations in PTCH or SMOH, indicating that mutations in one or the other of these genes are essential to the development of BCCs but do not dictate the histologic subtype. Furthermore, other genetic alterations known to occur in BCCs, such as p53 or RAS gene mutations, do not correlate with variation in biologic behavior. The purpose of this study is to identify the genetic causes and molecular correlates of different histologic subtypes of basal cell carcinomas. Specific aims are to 1) determine if genetic variation in members of the hedgehog pathway downstream from PTCH and SMO contribute to variation in biological behavior of these tumors, and 2) as an indirect method of examining other genetic and epigenetic phenomena in BCCs, use microarray analysis to try to classify these tumors and identify a set of genes whose expression predicts their biological behavior.

描述（由申请人提供）：皮肤基底细胞癌是迄今为止美国最常见的癌症类型，占所有新诊断恶性肿瘤的近一半。虽然这些肿瘤很少导致癌症死亡，但由于局部侵袭和组织破坏，它们与显著的发病率相关。基底细胞癌在大体和显微镜下的外观和生物学行为上变化极大，常见的组织病理学分类系统将肿瘤分为五个主要类别，这些类别在侵袭性、预后和对治疗的反应上不同。我的实验室分离出一个遗传性基底细胞癌的基因（人类斑片状癌;基因符号PTCH），并表明该基因在散发性基底细胞癌中也发生突变。完全类似于视网膜母细胞瘤建立的两次打击范例，几乎所有散发性基底细胞肿瘤都有两个体细胞来源的失活PTCH突变。PTCH是hedgehog信号转导通路的成员。在PTCH中缺乏突变的少数BCC在smoothened（SMO）中具有激活突变，smoothened（SMO）是刺猬途径的另一个成员，其蛋白质通常被补丁蛋白抑制。基底细胞癌的所有亚型都有PTCH或SMOH突变，表明这些基因中的一个或另一个突变对基底细胞癌的发展至关重要，但并不决定组织学亚型。此外，已知发生在BCC中的其他遗传改变，如p53或RAS基因突变，与生物学行为的变化无关。本研究的目的是确定基底细胞癌不同组织学亚型的遗传原因和分子相关性。具体目标是1）确定PTCH和SMO下游hedgehog途径成员的遗传变异是否有助于这些肿瘤生物学行为的变异，以及2）作为检查BCC中其他遗传和表观遗传现象的间接方法，使用微阵列分析来尝试对这些肿瘤进行分类，并鉴定一组其表达预测其生物学行为的基因。

项目成果

Simultaneous inhibition of COX-2 and 5-LOX activities augments growth arrest and death of premalignant and malignant human lung cell lines.

同时抑制 COX-2 和 5-LOX 活性可增强癌前和恶性人肺细胞系的生长停滞和死亡。

• 发表时间: 2007
• 期刊: Journal of experimental therapeutics & oncology
• 作者: Schroeder,ClaudiaP;Yang,Peiying;Newman,RobertA;Lotan,Reuben
• 通讯作者: Lotan,Reuben

Enhanced growth inhibition and apoptosis induction in NSCLC cell lines by combination of celecoxib and 4HPR at clinically relevant concentrations.

临床相关浓度的塞来昔布和 4HPR 组合可增强 NSCLC 细胞系的生长抑制和凋亡诱导。

• DOI: 10.4161/cbt.4.4.1618
• 发表时间: 2005
• 期刊: Cancer biology & therapy
• 影响因子: 3.6
• 作者: Sun,Shi-Yong;Schroeder,ClaudiaP;Yue,Ping;Lotan,Dafna;Hong,WaunK;Lotan,Reuben
• 通讯作者: Lotan,Reuben