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Serum Sarcosine, Variation in Sarcosine-related Genes and Subsequent Risk of Prostate Cancer

Principal Investigator
Name
Stella Koutros
Degrees
-
Institution
NCI, DCEG, OEEB
Position Title
-
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2009-0565
Initial CDAS Request Approval
Dec 15, 2009
Title
Serum Sarcosine, Variation in Sarcosine-related Genes and Subsequent Risk of Prostate Cancer
Summary
Emerging evidence suggests that prostate cancer progression is associated with changes in amino acid metabolism and methylation patterns. Using a metabolomic profiling approach, Sreekumar et al. (1) recently showed a strong link between urine and tissue sarcosine (a methylated derivative of the amino acid glycine), and prostate cancer in a small epidemiologic study (59 cases and 51 controls). They also showed that urine sarcosine levels had better predictive power for prostate cancer than prostate specific antigen (PSA) for patients with slightly to moderately elevated serum PSA levels (2-10 ng/ml). Furthermore, in vitro data from the same study support a direct role for sarcosine in the development of prostate cancer. Adding exogenous sarcosine or disabling the enzyme that degrades sarcosine imparted an invasive phenotype to benign prostate epithelial cells, whereas disabling the enzyme that converts glycine into sarcosine attenuated prostate cancer invasion. Furthermore, Sreekumar et al. (1) showed that sarcosine metabolism is regulated by the androgen signaling pathway via direct interactions of the androgen receptor transcriptional complex with sarcosine-related genes, providing further support for the importance of sarcosine in prostate cancer. This novel and potentially important sarcosine-prostate cancer link needs to be confirmed in a large epidemiologic study to clarify further the potential role of sarcosine. We propose to determine the association between baseline serum sarcosine and subsequent prostate cancer risk in a case-control study of prostate cancer (1,100 cases and 1,110 controls) nested in PLCO. Taking advantage of data from CGEMS/PLCO, we further propose to evaluate interactions between serum sarcosine and variations in four sarcosine-related genes (GNMT, DMGDH, SARDH, and PIPOX) previously genotyped as part of the CGEMS/PLCO Study on risk of prostate cancer. Findings from the proposed study could have a significant impact on our understanding of prostate cancer etiology and provide critical insight for prostate cancer prevention strategies.
Aims

Our primary hypothesis is that serum sarcosine levels are positively associated with the risk of 1) total prostate cancer and 2) aggressive prostate cancer. To test this hypothesis, we propose the following: Primary Aim: To determine the association between baseline serum sarcosine and total and aggressive prostate cancer. To address this aim, we will use a validated high-throughput liquid chromatography-mass spectrometry (LC-MS) assay to measure baseline serum sarcosine in 1,100 cases of prostate cancer (484 Non-aggressive and 616 Aggressive) and 1,100 controls nested within PLCO. To assess the effect of sarcosine, serum sarcosine will be included in logistic models of 1) total prostate cancer and 2) aggressive prostate cancer (Gleason score >7 or stage =3) along with potential confounders, such as age, dietary factors (intake of total calorie, red meat, lycopene, fish, calcium, vitamin D, a-linoleic acid, or vitamin E), body mass index, physical activity, smoking, alcohol use, family history of prostate cancer, and screening practices. Our secondary hypothesis is that variants in sarcosine-related genes are associated with prostate cancer risk and furthermore, that these genes can interact with serum sarcosine to modify the risk of prostate cancer. To test this hypothesis, we propose the following: Secondary Aim: To evaluate the association between 81 single nucleotide polymorphisms (SNPs) in four sarcosine-related genes (GNMT, DMGDH, SARDH, and PIPOX) and risk of prostate cancer and to further evaluate the joint effects of variation in sarcosine genes and serum levels of sarcosine on risk of prostate cancer. Within CGEMS, there are 81 SNPs previously genotyped within the four sarcosine-related genes (GNMT, DMGDH, SARDH, and PIPOX). We will seek approval from the DCEG Genotyping Review Committee (GRC) to gain access to these genotyping data as part of a CGEMS Value-added Study after receiving approval from EEMS for the serum sarcosine component.

Collaborators

Sonja Berndt (NCI, DCEG)
Lisa Chu (NCI, DCEG)
Robert Hoover (NCI, DCEG)
Ann Hsing (NCI, DCEG)
Wen-Yi Huang (NCI, DCEG)
Stella Koutros (NCI, DCEG) - Current Lead Investigator (3/4/2013)
Qizhai (James) Li (NCI, DCEG)
Tamra Meyer (NCI, DCEG)
Sabah Quraishi (NCI, DCEG)
Timothy Veenstra (NCI-Frederick (Advanced Technology Program))
Kai Yu (NCI, DCEG)

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