Epigenetics and Risk Factors for Breast and Ovarian Cancer in High Risk Women

高危女性乳腺癌和卵巢癌的表观遗传学和危险因素

基本信息

批准号：
8830850
负责人：
Jennifer Ferris
金额：
$ 4.16万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8830850
关键词：
Aberrant DNA Methylation Accounting Age BRCA1 gene BRCA2 gene Biological Markers Breast Breast Cancer Risk Factor Breast Feeding Cancer Etiology Cancer Family Case Fatality Rates Cessation of life Chemoprevention Contraceptive Usage DNA Methylation DNA Sequence Data Development Diagnosis Disease Epidemiology Epigenetic Process Ethnic Origin Family Family history of Family-Based Registry Female Gene Expression Gene Silencing Genes Goals Health Height Hereditary Breast Carcinoma Hereditary Malignant Neoplasm High Risk Woman Hormonal International Joints Laboratories Link Literature MLH1 gene Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mentors Methylation Modification Molecular Epidemiology Morbidity - disease rate Mutate Mutation Oral Contraceptives Outcome Ovarian Pathway interactions Pattern Plasma Prevention strategy Questionnaires Race Reporting Research Research Personnel Research Project Grants Research Proposals Research Training Resources Risk Risk Factors Role Screening for Ovarian Cancer Second Primary Cancers Statistical Methods Testing Tissues Training Translating Woman Work base breast cancer family registry breast cancer registry cancer epidemiology cancer risk career career development catalyst cohort experience high risk malignant breast neoplasm methylation pattern mortality multidisciplinary mutation carrier ovarian neoplasm parity population based reproductive screening tool tumor

项目摘要

DESCRIPTION (provided by applicant): In the U.S., breast cancer is the leading cause of cancer and second leading cause of cancer-death in women, while ovarian cancer is the most fatal gynecologic cancer. Breast and ovarian cancer have been found to co- occur. Both female cancers are associated with mutations in BRCA1 or BRCA2; however mutations in these genes account for only a small percent of all breast and ovarian cancers and less than half of all familial cancers. Thus, identifying other factors and pathways that are important to women at greatest risk of developing one or both cancers is crucial. Epigenetic modifications, such as DNA methylation, refer to heritable and modifiable markers that regulate gene expression without changing the underlying DNA sequence. Aberrant DNA methylation in specific genes can activate or silence genes critical to tumor development and progression; methylation of key genes has been observed in both breast and ovarian cancer. However, little research has been conducted to examine DNA methylation in high risk women from cancer families, many of whom do not carry a mutation in BRCA1 or BRCA2. Using the unique resource of the Breast Cancer Family Registry (BCFR), an international, multi-ethnic registry of breast and ovarian cancer families, I propose to examine the following aims: 1) To examine the association between hormonal, reproductive and anthropometric risk factors (OC use, parity, breastfeeding, and height) and breast and ovarian cancer co- occurrence using already existing retrospective data on 6,032 high-risk women; 2) To compare gene-specific DNA methylation in 8 genes (BRCA1, BRCA2, ER, PR, APC, RASSF1A, MLH1, P16) in tumor and adjacent non-tumor tissue from women with ovarian cancer (n=24 pairs), women with breast cancer (n=24 pairs), and women with breast and ovarian cancer (n=24 pairs); and 3) To compare gene-specific DNA methylation in genes found to be important in Aim 2, in the plasma of women who prospectively developed ovarian cancer compared to controls matched on age and date of diagnosis and race/ethnicity (n=100 pairs). The proposed training plan leverages my epidemiologic training by adding laboratory and biostatistical training relevant to molecular epidemiology and specifically to large scale DNA methylation analyses. The successful completion of these aims will provide critical data missing from the literature on the role of epigenetics and epidemiologic risk factors in the co-occurrence of breast and ovarian cancer. By examining complementary strategies using tissue and plasma-based markers, we will also robustly test whether markers in plasma can be used as potential screening for ovarian cancer risk in high-risk women. Completion of this proposed research project and training plan will provide essential data for future research projects that I will be able to use to further develop my career as an independent researcher.

描述（由申请人提供）：在美国，乳腺癌是癌症的主要原因，是女性癌症死亡的第二主要原因，而卵巢癌是最致命的妇科癌症。已经发现乳腺癌和卵巢癌发生。两种雌性癌症都与BRCA1或BRCA2中的突变有关。但是，这些基因中的突变仅占所有乳腺癌和卵巢癌的一小部分，不到所有家族性癌症的一半。因此，确定对患有一种或两种癌症最大风险的女性重要的其他因素和途径至关重要。表观遗传修饰（例如DNA甲基化）是指调节基因表达的可遗传和修改标记，而无需改变潜在的DNA序列。特定基因中的异常DNA甲基化可以激活或沉默基因对肿瘤发育和进展至关重要。在乳腺癌和卵巢癌中都观察到了关键基因的甲基化。但是，几乎没有进行研究以检查来自癌症家族的高风险妇女的DNA甲基化，其中许多人在BRCA1或BRCA2中不带突变。 Using the unique resource of the Breast Cancer Family Registry (BCFR), an international, multi-ethnic registry of breast and ovarian cancer families, I propose to examine the following aims: 1) To examine the association between hormonal, reproductive and anthropometric risk factors (OC use, parity, breastfeeding, and height) and breast and ovarian cancer co- occurrence using already existing retrospective data on 6,032 high-risk women; 2）在肿瘤中比较8个基因（BRCA1，BRCA2，ER，PR，APC，RASSF1A，MLH1，P16）中的基因特异性DNA甲基化和卵巢癌女性（n = 24对）中的肿瘤中的非肿瘤组织（N = 24对），患有乳腺癌的女性（n = 24对和乳腺癌）（N = 24 = 24 = 24 Pair）； 3）比较发现在AIM 2中很重要的基因中基因特异性DNA甲基化，这些基因在前瞻性发展卵巢癌的血浆中与诊断和种族/种族/种族/种族的年龄和日期相比（n = 100对）相比。提出的培训计划通过添加与分子流行病学相关的实验室和生物统计培训来利用我的流行病学培训比例DNA甲基化分析。这些目标的成功完成将提供有关表观遗传学和流行病学危险因素在乳腺癌和卵巢癌共呈现中的作用的文献中缺少的关键数据。通过使用组织和基于等离子体的标记来检查互补策略，我们还将坚固地测试血浆中的标记是否可以用作高危女性卵巢癌风险的潜在筛查。该建议的研究项目和培训计划的完成将为未来的研究项目提供必要的数据，我将能够进一步发展自己作为独立研究人员的职业。