FGFR2 MUTATIONS IN INTERMEDIATE RISK ENDOMETRIAL CANCERS

中危子宫内膜癌中的 FGFR2 突变

• 批准号: 7644524
• 负责人: Paul Joseph Goodfellow
• 金额: $ 11.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-25 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644524
• 关键词: Address; Adjuvant; Adjuvant Therapy; Biological Response Modifier Therapy; Body of uterus; Cancer Patient; Cell Death; Cell Line; Cisplatin; Clinical; Clinical Data; Clinical Management; Clinical Trials; Cytotoxic agent; DNA; Data; Diagnosis; Diagnostic Neoplasm Staging; Disease; Doxorubicin; Endometrial; Endometrial Carcinoma; Event; FGFR2 gene; Fibroblast Growth Factor Receptor 2; Fibroblast Growth Factor Receptors; Frequencies; Funding; Genetic Models; Gynecologic; Gynecologic Oncology Group; Hormonal; Hysterectomy; Incidence; Link; Malignant Neoplasms; Mediating; Mismatch Repair; Modality; Molecular; Molecular Abnormality; Mutation; Mutation Analysis; Mutation Detection; Mutation Spectra; Oncogenes; Operative Surgical Procedures; Outcome; Paclitaxel; Pathway interactions; Patients; Play; Population; Proteins; Protocols documentation; Radiation; Receptor Protein-Tyrosine Kinases; Receptor Tyrosine Kinase Gene; Recurrence; Recurrent disease; Risk; Role; Screening procedure; Specimen; Staging; Survival Rate; Testing; Therapeutic; Time; Tumor stage; United States; Uterine Cancer; Woman; Work; base; chemotherapy; clinically significant; effective therapy; high risk; inhibitor/antagonist; mortality; novel; outcome forecast; public health relevance; small hairpin RNA; success; therapeutic target; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in the United States. Approximately 39,800 new cases of cancer of the uterine corpus will be diagnosed and 7,400 women will die of this disease in 2007. The incidence in the United States is among the highest in the world. Fortunately, most women present with early stage disease and surgery alone (hysterectomy) is curative. The overall five-year survival rate for endometrial cancer patients is estimated at 80-85%. Despite the high cure rate, endometrial cancer remains a clinically challenging disease. Adjuvant therapies (radiation, hormonal, chemotherapy, or combinations) for women with advanced stage, progressive or recurrent disease are not very effective at this time. The median survival after recurrence is ten months and the five-year survival for patients who have recurred is <15%. Effective treatments for advanced and recurrent endometrial carcinoma remain to be defined. New biologic or targeted therapies based on an understanding of the underlying causes of disease hold promise for better outcomes for women with endometrial cancer. We recently determined activating mutations in the FGFR2 oncogene are present in approximately 15% of endometrioid endometrial cancers. Anti-FGFR therapeutics are already in clinical trails for other malignancies and may prove useful in the treatment of endometrial cancers. We propose to analyze endometrial cancers from the Gynecologic Oncology Group Protocol 210 to better understand the clinical significance of FGFR2 mutations and the relationship between activation of FGFR2 and loss of DNA mismatch repair, a key early event in the initiation of ~30% of endometrioid endometrial cancers. Two specific aims are proposed: Specific Aim 1: Determine the role FGFR2 mutations play in intermediate and high risk endometrial cancers. We will assess the rate and spectrum of mutations by direct sequencing and test targeted mutation detection in ~550 endometrioid cancer specimens from GOG-210. We will determine the relationship between FGFR2 mutation and clinicopathologic variables including disease-free and overall survival. Specific Aim 2: Determine the relationship between loss of DNA mismatch repair and FGFR2 mutation. Our preliminary studies suggest FGFR2 mutation may be more common in tumors lacking DNA mismatch repair. Understanding what pathways are dysregulated in cancers will be critical to developing biologic therapies. Understanding of the clinical significance of FGFR2 mutations in endometrial cancer is a critical first step towards determining whether FGFR inhibitors could be useful in treating patients with endometrial cancer. PUBLIC HEALTH RELEVANCE: Our collaborative group recently determined activating mutations in the fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinase gene are frequent in uterine endometrial cancers. The FGFR2 gene product is a potential therapeutic target, with several biologics with activity against FGFR2 already in clinical trials. In this proposal we will evaluate endometrial cancers from the NCI-funded Gynecologic Oncology Group Protocol 210 "A molecular staging study of endometrial carcinoma" for mutations in FGFR2. We will determine the frequency and spectrum of mutations and the relationship between mutations and outcome. Furthermore, we will determine how FGFR2 mutations are related to important clinical variables and other molecular abnormalities in endometrial cancers. These studies are an important first step in considering anti-FGFR2 treatments for endometrial cancer.

描述（由申请人提供）：子宫内膜癌是美国最常见的妇科恶性肿瘤。2007年，将诊断出约39 800个子宫体癌新病例，7 400名妇女将死于这种疾病。美国的发病率是世界上最高的。幸运的是，大多数妇女都患有早期疾病，仅手术（子宫切除术）是可以治愈的。子宫内膜癌患者的总体五年生存率估计为80- 85%。尽管治愈率很高，但子宫内膜癌仍然是临床上具有挑战性的疾病。辅助治疗（放射，激素，化疗或组合）的妇女与先进的阶段，进行性或复发性疾病是不是很有效，在这个时候。复发后的中位生存期为10个月，复发患者的5年生存率<15%。晚期和复发性子宫内膜癌的有效治疗仍有待确定。基于对疾病根本原因的理解的新生物或靶向疗法有望为子宫内膜癌患者带来更好的结局。我们最近确定FGFR 2癌基因的激活突变存在于大约15%的子宫内膜样癌中。抗FGFR疗法已经在其他恶性肿瘤的临床试验中，并可能证明在子宫内膜癌的治疗中是有用的。我们建议从妇科肿瘤组方案210中分析子宫内膜癌，以更好地了解FGFR 2突变的临床意义以及FGFR 2激活与DNA错配修复缺失之间的关系，DNA错配修复缺失是约30%子宫内膜样癌发生的关键早期事件。提出了两个具体目标：具体目标1：确定FGFR 2突变在中高危子宫内膜癌中的作用。我们将通过直接测序评估突变率和谱，并在来自GOG-210的约550例类胶质瘤标本中进行靶向突变检测。我们将确定FGFR 2突变与临床病理变量（包括无病生存期和总生存期）之间的关系。具体目标2：确定DNA错配修复缺失与FGFR 2突变之间的关系。我们的初步研究表明FGFR 2突变可能在缺乏DNA错配修复的肿瘤中更常见。了解癌症中哪些途径失调对于开发生物疗法至关重要。了解FGFR 2突变在子宫内膜癌中的临床意义是确定FGFR抑制剂是否可用于治疗子宫内膜癌患者的关键第一步。公共卫生相关性：我们的合作小组最近确定成纤维细胞生长因子受体2（FGFR 2）受体酪氨酸激酶基因的激活突变在子宫内膜癌中很常见。FGFR 2基因产物是一种潜在的治疗靶点，几种具有抗FGFR 2活性的生物制剂已经在临床试验中。在本提案中，我们将从NCI-FGFR 2基因突变的研究中评估子宫内膜癌。我们将确定突变的频率和谱以及突变与结果之间的关系。此外，我们将确定FGFR 2突变如何与子宫内膜癌的重要临床变量和其他分子异常相关。这些研究是考虑抗FGFR 2治疗子宫内膜癌的重要第一步。