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The Impact of DNA Damage Repair Abnormalities in Prostate Cancer

DNA 损伤修复异常对前列腺癌的影响

基本信息

批准号：
10003188
负责人：
KENNETH OFFIT
金额：
$ 178.34万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10003188
关键词：
Address Cancer Etiology Cessation of life Clinical Clinical Investigator DNA Repair DNA Repair Gene DNA Repair Pathway Data Diagnosis Disease Early Intervention Epidemiologist Ethnic Origin Ethnic group Frequencies Genes Genetic Variation Goals Individual Inherited Intervention Localized Disease Malignant Neoplasms Malignant neoplasm of prostate Molecular Abnormality Outcome Pathogenicity Pathologist Pathway interactions Patient Care Patient-Focused Outcomes Patients Play Prostate Cancer therapy Protein Truncation Research Personnel Role Scientist Screening for Prostate Cancer Series Testing Therapeutic Time United States Variant Vision advanced disease adverse outcome base cancer diagnosis castration resistant prostate cancer clinically significant disease natural history gene repair high risk improved improved outcome insertion/deletion mutation men multidisciplinary mutational status precision medicine programs prostate cancer risk screening systemic intervention treatment strategy tumor

项目摘要

SUMMARY/ABSTRACT Prostate cancer is the most commonly diagnosed cancer among men in the United States, with an anticipated 164,690 men being diagnosed in 2018. It is also one of the leading causes of cancer death, with approximately 29,430 deaths anticipated in 2018, usually as a result of metastatic castration-resistant prostate cancer (mCRPC). Pathogenic variants in DNA damage repair (DDR) pathway genes are prevalent in a substantial subset of men who develop mCRPC. These germline or somatic genetic abnormalities, primarily insertions and deletions resulting in protein truncations that interfere with DDR, occur in 20-25% of men with mCRPC. While several studies are underway to leverage these findings for men at the latest stages of prostate cancer, genetic variation in the DDR pathway has not yet been fully characterized for men with localized prostate cancer. While there is increasing evidence that some DDR gene aberrations may be associated with aggressive prostate cancer, this also has not been fully characterized. In the United States, where prostate cancer screening is common, over 90% of patients present initially with localized disease. It is at this point in the natural history of the disease when intervention can have the most profound impact. Thus, a major focus of this proposal is understanding the spectrum of DDR gene aberrations that promote aggressive cancers, particularly in men with high-risk localized and oligometastatic disease. Retrospective series demonstrate that DDR variants occur with low frequency in men with low-risk prostate cancer and with higher frequency in men with high-risk localized prostate cancer. This has wide-ranging clinical implications. For instance, mutational status could be used to identify those at highest risk of developing lethal prostate cancer, and therapy could be optimized based on tumor or germline findings. In addition, targeted screening could be implemented to identify those at highest risk of aggressive disease and provide an opportunity for early intervention. The overarching goal of this program is to increase our understanding of the spectrum of DDR gene aberrations that are associated with adverse outcomes in high-risk localized and oligometastatic prostate cancer. This will allow us to optimize the therapeutic approach to patients who have DDR aberrations, to detect and treat lethal disease early, and to improve outcomes for patients and their relatives who carry germline aberrations. In order to achieve our goal, we have assembled a multi-institutional and multidisciplinary group of investigators, including clinical investigators, epidemiologists, statisticians, pathologists, clinical geneticists, computational biologists, bioinformaticians, and basic scientists. Our specific aims are to determine the association between long-term clinical outcome and pathogenic germline and somatic variants in DDR genes across different ethnic groups, to develop treatment strategies for patients with germline or somatic alterations in DDR pathways, and to evaluate the functional significance of different alterations in DDR genes.

摘要/文摘