Identifying inherited endometrial cancer & the environmental and genetic factors

识别遗传性子宫内膜癌

• 批准号: 7727350
• 负责人: Paul Joseph Goodfellow
• 金额: $ 12.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727350
• 关键词: Address; Adjuvant Therapy; Body of uterus; Cancer Biology; Cancer Burden; Cancer Patient; Clinical; Colon Carcinoma; Colonoscopy; Colorectal; DNA; DNA Repair Gene; Data; Defect; Detection; Diagnosis; Disease; Disease remission; Endometrial; Endometrial Carcinoma; Environmental Risk Factor; Epidemiological Factors; Epigenetic Process; Extended Family; Family; Family history of; Family member; Frequencies; Gene Silencing; Genes; Genetic; Gynecologic; Gynecologic Oncologist; Gynecologist; Health Professional; Hereditary Nonpolyposis Colorectal Neoplasms; Incidence; Individual; Inherited; Instruction; Lead; MLH1 gene; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Methylation; Mismatch Repair; Molecular; Morbidity - disease rate; Mutation; Nested Case-Control Study; Ovarian; Patients; Predisposition; Prevention; Recurrent disease; Relative (related person); Reproduction spores; Risk; Risk Assessment; Screening procedure; Staging; Survival Rate; Syndrome; Treatment Protocols; United States; Uterine Cancer; Variant; Woman; Work; epidemiologic data; gene repair; improved; molecular phenotype; mortality; mutation carrier; novel strategies; proband; promoter; tumor

Endometrial cancer is the most common gynecologic malignancy In the US. Most endometrial cancers are sporadic. However, some patients have an inherited cancer susceptibility, usually due to mutation in a DNA mismatch repair gene. These women have Lynch syndrome. They are at much Increased risk for colorectal and other malignancies, as are their family members. Identification of endometrial cancer patients with Lynch syndrome is important to the proband and her family. Intensified cancer surveillance is required for individuals with Lynch syndrome mutations. In particular, colonic surveillance reduces cancer burden. Although health professionals are increasingly aware of Lynch syndrome, most endometrial cancer probands with Lynch syndrome likely go undetected. Molecular screening strategies should help to address this deficiency, but at present, the best approach is unknown. The importance of DNA mismatch repair abnormalities in endometrial cancer is further evidenced by the high frequency of acquired (somatic) defects, most frequently epigenetic silencing of the MLH1 repair gene. Our group has shown inherited variation in the MLH1 gene itself is associated with risk for abnormal methylation and gene silencing, and have data suggesting specific environmental factors contribute to risk. The aims for this project address important questions regarding mismatch repair abnormalities in endometrial cancer. (1) Develop of a molecular screening regimen to compliment family history risk assessment for the detection of Lynch syndrome. >3,000 endometrial cancers from the GOG-210 study will be evaluated using MSI, IHC, promoter methylation and gene sequencing. (2) Better estimate the frequency of Lynch syndrome among endometrial cancer patients and determine the clinicopathologic significance of mismatch repair defects. Detailed clinical, medical and family history and epidemiologic data from the GOG-210 study will be correlated with molecular phenotypes. (3) Further refine the relationship between inherited variation in the MLHI DNA repair gene and epigenetic silencing of MLHI in sporadic endometrial cancer. A nested case- control study will define key genetic and environmental factor interactions. The work proposed will improve identification of Lynch syndrome and with that reduce cancer burden, and better define key genetic and environmental factor leading to somatic (acquired) inactivation of mismatch repair in endometrial cancers. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.

子宫内膜癌是美国最常见的妇科恶性肿瘤。大多数子宫内膜癌是 零星的。然而，一些患者具有遗传性癌症易感性，通常是由于DNA突变造成的 错配修复基因这些女人有林奇综合症。他们患结肠直肠癌的风险大大增加 和其他恶性肿瘤，以及他们的家庭成员 鉴别子宫内膜癌Lynch综合征患者对先证者及其家属具有重要意义。 对于Lynch综合征突变的个体，需要加强癌症监测。特别是， 结肠监测减少癌症负担。尽管卫生专业人员越来越意识到林奇 Lynch综合征的子宫内膜癌先证者中，大多数可能未被发现。分子 筛查策略应有助于解决这一缺陷，但目前尚不清楚最佳方法。 DNA错配修复异常在子宫内膜癌中的重要性进一步得到了高表达的证实。 获得性（体细胞）缺陷的频率，最常见的是MLH 1修复基因的表观遗传沉默。我们 一组研究表明MLH 1基因本身的遗传变异与异常甲基化的风险有关 和基因沉默，并有数据表明特定的环境因素有助于风险。目标是 该项目解决了有关子宫内膜癌错配修复异常的重要问题。 (1)制定分子筛查方案，以补充检测的家族史风险评估 Lynch综合征来自GOG-210研究的> 3，000例子宫内膜癌将使用MSI，IHC， 启动子甲基化和基因测序。(2)更好地估计Lynch综合征的频率， 子宫内膜癌患者的错配修复缺陷，并确定临床病理意义。 GOG-210研究的详细临床、病史和家族史以及流行病学数据将在 与分子表型相关。(3)进一步细化遗传变异与基因组中 散发性子宫内膜癌中MLHI DNA修复基因和MLHI的表观遗传沉默一个嵌套的案件- 对照研究将确定关键的遗传和环境因素的相互作用。建议的工作将得到改善 鉴别Lynch综合征并与降低癌症负担，以及更好地确定关键遗传和 导致子宫内膜癌中错配修复体细胞（获得性）失活的环境因素。 相关性（参见说明）： 拟议的工作将提高对子宫内膜癌生物学的了解，并带来新的 检测、预防和治疗子宫癌的方法， 发病率和死亡率。