||1P01CA228696-01A1 Interpret this number
||Sloan-Kettering Inst Can Research
||The Impact of DNA Damage Repair Abnormalities in Prostate Cancer
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.
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