Colorectal Cancer
Conditions
Brief summary
Based on the magnesium tolerance test (MTT, gold standard for assessing magnesium (Mg) status), it was found that over 50% of participants in the US exhibited Mg deficiency. Studies suggest that the relationship between high Mg intake and disease risks may be varied by an individual's Mg status. Despite its importance, MTT is not commonly employed in routine clinical practice or research studies. Instead, serum Mg levels are typically used for clinical diagnosis, although this method has shown limited efficacy in identifying Mg deficiency accurately. Consequently, there is a pressing need to develop practical, sensitive, and specific biomarkers that can efficiently identify individuals with Mg deficiency. It is known that DNA methylation changes are inducible by environmental exposures, including nutrients, and reversible when the exposure disappears. There are two major types of DNA methylation modifications, 5-hydroxymethylcytosine (5-hmC) and 5-methylcytosine (5-mC). 5-mC is often associated with suppressed gene expression. 5-hmC, generated by the oxidation of 5-mC, is specifically enriched in expressed genes and play a critical role in activating and/or maintaining gene expression. We plan identify 5-hmC and 5-mC for Mg deficiency by a 4- phase comprehensive epigenome-wide association study (EWAS) using the samples collected in the Personalized Prevention of Colorectal Cancer Trial \[PPCCT, R01CA149633; PI, Dai & Yu\] . The parent trial \[NCT04196023\] that supports this ancillary research is a randomized controlled trial to evaluate the efficacy of reducing the Ca:Mg ratio among those who consume high Ca:Mg ratio diets to decrease the risk of colorectal cancer. For this ancillary trial research, the investigators are examining ancillary measures of Changes of Cytosine Modification in TMPRSS2.
Interventions
DIETARY_SUPPLEMENTMagnesium glycinate
Oral administration of magnesium glycinate daily for 12 weeks
DIETARY_SUPPLEMENTPlacebo
Oral administration of identical-appearing placebo daily for 12 weeks
Sponsors
National Cancer Institute (NCI)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
1. Participants from our parent study (Personalized Prevention of Colorectal Cancer Trial, NCT#01105169, IRB#100106); 2. Participants consent to store/share biospecimens for future research.
Exclusion criteria
1\. Participants cannot provide their blood samples in the parent study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | 12 Weeks | Increases in 5-mC methylation at cg16371860 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-mC methylation changes=value at 12 weeks minus value at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | 12 Weeks | Decreases in 5-hmC methylation at cg16371860 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-hmC methylation changes=value at 12 weeks minus value at baseline. |
| Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | 12 Weeks | Increases in 5-mC methylation at cg26337277 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-mC methylation changes=value at 12 weeks minus value at baseline. |
| Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | 12 Weeks | Decreases in 5-hmC methylation at cg26337277 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-hmC methylation changes=value at 12 weeks minus value at baseline. |
Participant flow
Recruitment details
Participants, aged 40-85 y, with colorectal polyp or polyp-free individuals with high risk of colorectal cancer and had a calcium intake of ≥700 and \<2000 mg/d, and their calcium-to-magnesium intake ratio was \>2.6 (based on baseline two 24-hour dietary recalls) and have blood samples were recruited from Vanderbilt patient sources from March 11, 2011 to Jan 30, 2016 .
Participants by arm
| Arm | Count |
|---|---|
| Magnesium Treatment Participants were assigned to magnesium glycinate
Magnesium glycinate: Oral administration of magnesium glycinate daily for 12 weeks | 119 |
| Placebo Participants were assigned to placebo group
Placebo: Oral administration of identical-appearing placebo daily for 12 weeks | 120 |
| Total | 239 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Magnesium Treatment |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 42 Participants | 79 Participants | 37 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants | 160 Participants | 82 Participants |
| Age, Continuous | 61.2 years STANDARD_DEVIATION 8.1 | 60.7 years STANDARD_DEVIATION 7.9 | 60.1 years STANDARD_DEVIATION 7.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 119 Participants | 236 Participants | 117 Participants |
| Region of Enrollment United States | 120 participants | 239 participants | 119 participants |
| Sex: Female, Male Female | 58 Participants | 113 Participants | 55 Participants |
| Sex: Female, Male Male | 62 Participants | 126 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 124 | 0 / 126 |
| other Total, other adverse events | 4 / 124 | 3 / 126 |
| serious Total, serious adverse events | 0 / 124 | 0 / 126 |
Outcome results
Primary
Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo
Increases in 5-mC methylation at cg16371860 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-mC methylation changes=value at 12 weeks minus value at baseline.
Time frame: 12 Weeks
Population: Overall analysis and stratified analysis by age (\<65 years, ≥ 65 years)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | All | 0.007 units on CpG sites | Standard Deviation 0.024 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | Age<65 | 0.012 units on CpG sites | Standard Deviation 0.022 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | Age≥65 | -0.004 units on CpG sites | Standard Deviation 0.025 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | All | -0.001 units on CpG sites | Standard Deviation 0.025 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | Age<65 | -0.002 units on CpG sites | Standard Deviation 0.022 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg16371860) by Magnesium Treatment Versus Placebo | Age≥65 | -0.001 units on CpG sites | Standard Deviation 0.031 |
p-value: <0.05Regression, Linear
Secondary
Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo
Decreases in 5-hmC methylation at cg16371860 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-hmC methylation changes=value at 12 weeks minus value at baseline.
Time frame: 12 Weeks
Population: Overall analysis and stratified analysis by age (\<65 years, ≥ 65 years)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | All | -0.001 units on CpG sites | Standard Deviation 0.002 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | Age<65 | -0.001 units on CpG sites | Standard Deviation 0.002 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | Age≥65 | -0.000 units on CpG sites | Standard Deviation 0.002 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | All | 0.000 units on CpG sites | Standard Deviation 0.002 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | Age<65 | 0.000 units on CpG sites | Standard Deviation 0.002 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg16371860) by Magnesium Treatment Versus Placebo | Age≥65 | 0.000 units on CpG sites | Standard Deviation 0.002 |
p-value: >0.05Regression, Linear
Secondary
Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo
Decreases in 5-hmC methylation at cg26337277 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-hmC methylation changes=value at 12 weeks minus value at baseline.
Time frame: 12 Weeks
Population: Overall analysis and stratified analysis by age (\<65 years, ≥ 65 years)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | All | -0.000 units on CpG sites | Standard Deviation 0.001 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | Age<65 | -0.000 units on CpG sites | Standard Deviation 0.001 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | Age≥65 | -0.000 units on CpG sites | Standard Deviation 0.001 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | All | 0.000 units on CpG sites | Standard Deviation 0.001 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | Age<65 | 0.000 units on CpG sites | Standard Deviation 0.001 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-hmC at cg26337277) by Magnesium Treatment Versus Placebo | Age≥65 | 0.000 units on CpG sites | Standard Deviation 0.001 |
p-value: =0.08Regression, Linear
Secondary
Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo
Increases in 5-mC methylation at cg26337277 (the promoter) indicate a hindered process of transcription initiation and, subsequently, lower levels of TMPRSS2 expression. 5-mC methylation changes=value at 12 weeks minus value at baseline.
Time frame: 12 Weeks
Population: Overall analysis and stratified analysis by age (\<65 years, ≥ 65 years)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | All | 0.000 units on CpG sites | Standard Deviation 0.001 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | Age<65 | -0.000 units on CpG sites | Standard Deviation 0.002 |
| Magnesium Treatment | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | Age≥65 | 0.000 units on CpG sites | Standard Deviation 0.001 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | All | 0.000 units on CpG sites | Standard Deviation 0.002 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | Age<65 | -0.000 units on CpG sites | Standard Deviation 0.002 |
| Placebo | Changes of Cytosine Modification in TMPRSS2 (5-mC at cg26337277) by Magnesium Treatment Versus Placebo | Age≥65 | 0.000 units on CpG sites | Standard Deviation 0.002 |
p-value: >0.05Regression, Linear