Impact of Genomics on Disparities in Breast Cancer Radiosensitivity

基因组学对乳腺癌放射敏感性差异的影响

• 批准号: 7799641
• 负责人: Jennifer J Hu
• 金额: $ 61.01万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799641
• 关键词: Acute; Adjuvant Radiotherapy; Adverse effects; Adverse reactions; African American; American; Amino Acid Sequence; Amino Acids; Angiogenesis Pathway; Apoptosis; Benefits and Risks; Biological Assay; Biological Markers; Breast; Cancer Etiology; Cancer Patient; Cell Cycle; Cell Cycle Regulation; Cessation of life; Clinical; Clinical Treatment; Comet Assay; Cosmetics; DNA Damage; DNA Repair; Data; Development; Developmental Process; Disease; Edema; Epidemiologist; Ethnic group; Evaluation; Follow-Up Studies; Funding; Genes; Genetic; Genetic Models; Genetic Variation; Genomics; Goals; Hispanics; Immunology; Individual; Inflammation; Intensity-Modulated Radiotherapy; Interdisciplinary Study; Intervention; Ionizing radiation; Knowledge; Late Effects; Lead; Learning; Logit Models; Malignant Neoplasms; Minority; Modeling; Molecular; Mutation; Normal tissue morphology; Not Hispanic or Latino; Oncologist; Outcome; Pain; Pathway interactions; Patients; Peptide Sequence Determination; Phenotype; Phosphorylation; Population; Population Study; Positioning Attribute; Postoperative Period; Progression-Free Survivals; Quality of life; Radiation Oncologist; Radiation Tolerance; Radiation therapy; Reaction; Recruitment Activity; Recurrence; Research; Resistance; Sampling; Second Primary Cancers; Signal Transduction; Single Nucleotide Polymorphism; Skin; Staging; Surgeon; Target Populations; Testing; Trees; Underserved Population; Woman; Work; breast lumpectomy; cancer diagnosis; cancer health disparity; cancer risk; cell motility; cohort; data mining; design; dosimetry; effective intervention; experience; follow-up; functional genomics; gene interaction; genetic analysis; genome-wide; high risk; high throughput technology; improved; indexing; malignant breast neoplasm; medically underserved population; mortality; outcome forecast; public health relevance; racial and ethnic; response; standard care; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. Lumpectomy followed by radiotherapy (RT) has significantly improved survival. However, about 30% of patients develop a Grade 2 or worse early or late skin reaction, pain, breast edema and poor cosmetic results that impact quality of life. Inter-individual variability in the development of RT-induced adverse reactions in normal tissue is well-documented for both acute and late effects. African-American (AA) and underserved populations are less likely than Whites to receive the recommended adjuvant RT, if treated, have a higher risk for developing RT-related side effects and worse clinical outcome. To achieve our long-term goals in improving quality of life, clinical outcome, and overcoming breast cancer disparities, we will use a genome- wide approach to test genomic prediction models for RT-induced adverse reactions and recurrence in three racial/ethnic populations. We will test a new paradigm that multiple genetic variations and functional phenotypes contribute to radiation sensitivity that may predict RT-induced side effects and clinical outcome. Investigating this new paradigm will develop powerful tools in identifying high-risk populations and targets for personalized intervention and treatment. Aim 1 will evaluate polygenic models of RT-induced early adverse skin reactions (EASRs) in 1000 breast cancer patients with a comprehensive evaluation of genome-wide nonsynonymous single nucleotide polymorphisms (nsSNPs; n=21,877). Aim 2 will evaluate the association between RT-induced EASRs and three functional DNA damage/repair phenotypes. Aim 3 will develop polygenic models of genome-wide nsSNPs in predicting RT-induced late side effects and/or recurrence in a breast cancer cohort of 850 women with a median follow up of 8 years (range 4-12 years). The outcome of the proposed research will advance our scientific knowledge in the accurate assessment of prognosis in cancer patients, which is crucial to controlling the suffering and death due to breast cancer. Prediction models provide an important approach to assessing cancer risk, progression, quality of life, and prognosis. These prediction models may identify individuals at high risk of developing adverse reactions or recurrence who may benefit from targeted treatment or other interventions. They also may enable the development of benefit-risk indices that will aid in the design and planning of clinical treatment. The proposed research will use a hypothesis- driven approach to integrate genetic and functional biomarkers in developing optimal prediction models of RT- induced adverse reactions and recurrence. The outcome will target effective intervention and treatment strategies, and ultimately improve quality of life and progression-free survival in breast cancer patients, particularly in minority and underserved populations with more aggressive disease and worse clinical outcome. This will be the largest and most complete genetic analysis of RT-related clinical outcome to date, and will move the field significantly towards the goal of more effective, personalized therapy for breast cancer patients. PUBLIC HEALTH RELEVANCE: Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. The long-term goal of this study is to improve quality of life, clinical outcome, and breast cancer disparities. The proposed research will use a genome-wide approach to develop and validate genomic prediction models for radiotherapy-induced early and late side effects as well as local-regional recurrence in three racial/ethnic populations. The outcome of the proposed research will advance our scientific knowledge in the accurate assessment of prognosis and response to therapy in cancer patients, which is crucial to controlling the suffering and death due to breast cancer.

描述(由申请人提供)： 乳腺癌是美国女性最常被诊断的癌症，也是导致癌症死亡的第二大原因。肿瘤切除后放射治疗(RT)显著提高了存活率。然而，大约30%的患者在早期或晚期出现2级或更严重的皮肤反应、疼痛、乳房浮肿和不良的美容效果，这些都会影响生活质量。在正常组织中，放射治疗引起的不良反应发生的个体间差异对于急性和晚期影响都有很好的文献记载。与白人相比，非裔美国人(AA)和服务不足的人群接受推荐的辅助RT的可能性较小，如果接受治疗，发生RT相关副作用的风险更高，临床结果更差。为了实现我们在改善生活质量、临床结果和克服乳腺癌差异方面的长期目标，我们将使用全基因组方法在三个种族/民族人群中测试RT引起的不良反应和复发的基因组预测模型。我们将测试一种新的范式，即多种基因变异和功能表型有助于辐射敏感性，可能预测RT诱导的副作用和临床结果。对这一新范式的研究将开发出确定高危人群和个性化干预和治疗目标的强大工具。目的1综合评价全基因组非同义单核苷酸多态(nsSNPs；n=21,877)，对1000例乳腺癌患者进行RT诱导早期皮肤不良反应(EASR)的多基因模型评价。目的2将评估RT诱导的EASRs与三种功能DNA损伤/修复表型之间的关系。AIM 3将开发全基因组nsSNPs的多基因模型，以预测乳腺癌队列中850名女性接受RT治疗后的晚期副作用和/或复发，平均随访时间为8年(范围为4-12年)。这项研究的结果将促进我们对癌症患者预后的准确评估的科学知识，这对于控制乳腺癌造成的痛苦和死亡至关重要。预测模型提供了评估癌症风险、进展、生活质量和预后的重要方法。这些预测模型可以确定可能受益于靶向治疗或其他干预措施的不良反应或复发的高风险个体。它们还可能使效益-风险指数的发展成为可能，这将有助于临床治疗的设计和规划。这项拟议的研究将使用假设驱动的方法，将遗传和功能生物标记物整合在一起，开发出RT引起的不良反应和复发的最佳预测模型。结果将以有效的干预和治疗策略为目标，并最终提高乳腺癌患者的生活质量和无进展生存率，特别是在疾病更具侵袭性、临床结果更差的少数族裔和服务不足的人群中。这将是迄今为止对RT相关临床结果的最大和最完整的基因分析，并将大大推动该领域朝着为乳腺癌患者提供更有效、个性化治疗的目标迈进。 公共卫生相关性： 乳腺癌是美国女性最常被诊断的癌症，也是导致癌症死亡的第二大原因。这项研究的长期目标是改善生活质量、临床结果和乳腺癌差异。这项拟议的研究将使用全基因组方法来开发和验证三个种族/民族人群中放射治疗引起的早期和晚期副作用以及局部区域复发的基因组预测模型。这项拟议的研究结果将促进我们在准确评估癌症患者的预后和治疗反应方面的科学知识，这对于控制乳腺癌造成的痛苦和死亡至关重要。