Colorectal Cancer, GENE EXPRESSION
Conditions
Keywords
VITAMIN D
Brief summary
AIMS To identify the underlying mechanism by which Vitamin D reduces colorectal cancer risk. OBJECTIVES To demonstrate the effects of vitamin D supplementation on serum vitamin D levels. To demonstrate dynamic changes in gene expression in response to vitamin D. To demonstrate the mechanism underlying the gene-environment interaction of vitamin D, susceptibility genetic variants (risk genes) and colorectal cancer.
Detailed description
Through National Health Service (NHS) clinical services in colorectal surgery and oncology, patients will be identified and recruited from surgical wards or surgical/oncology out-patient clinics. A sample of participants with and without a new or previous diagnosis of colorectal cancer will be included for comparison. Participation will consist of two events in the majority of participants. Firstly a in the surgical ward or clinic lasting no longer than 20 minutes in which the research will be discussed and informed consent gained. A blood sample will be taken prior to the conclusion of recruitment and a rectal biopsy taken using a rigid sigmoidoscopy which may or may not be required as part of their routine clinical assessment. Participants will be asked to take pharmaceutical grade vitamin D tablets for 3 months. After 12 weeks of vitamin D supplementation, a final blood sample and rectal biopsy will be taken. If patients would like to contribute but cannot or would prefer not to take vitamin D, or cannot return for future sampling, a single sampling will be offered. This participant would undergo blood sampling and rectal biopsy as above. After this no further events would occur.
Interventions
DIETARY_SUPPLEMENTFULTIUM D3 VITAMIN D3
VITAMIN D3 SUPPLEMENT
Sponsors
Cancer Research UK
Medical Research Council
University of Edinburgh
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
SINGLE GROUP INTERVENTION STUDY
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Aged 16 years or over. * Resident of the United Kingdom
Exclusion criteria
1. The inability to provide informed consent. 2. Under the age of 16 years. 3. A non-UK resident. 4. Patients who may be at increased risk from rigid sigmoidoscopy: * Individuals who are taking anti-coagulation medication. * Individuals with platelet disease or other bleeding issues. * Individuals with a history of a significant rectal bleed. * Suspected or known bowel perforation * Anal stenosis * Acute peritonitis * Colonic necrosis * Toxic megacolon * Acute severe diverticulitis * Diverticular abscess * Recent colonic surgery * Anal fissure * Severe coagulopathy * Anticoagulant therapy * Severe thrombocytopenia * Severe neutropenia 5. Patients who may be at increased risk from Vitamin D supplementation would not be included in the intervention arm but could still be included in the single sample arm: * Kidney disease * High levels of calcium in the blood * Atherosclerosis * Sarcoidosis * Histoplasmosis * Over-active parathyroid gland (hyperparathyroidism) * Lymphoma * Currently taking thiazide diuretics, digoxin or other cardiac glycosides * Known allergy to nuts ( as peanut oil contained within vitamin D preparations) * Female subjects of child bearing age who are not taking effective contraception during the period of the trial 6. Patients in whom vitamin D levels may be unpredictable * Individuals already established on supplementary Vitamin D. * Individuals recently returned to the UK from an overseas holiday. * Individuals who have recently lived abroad. * Patients on anti-epileptic medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Genes Significantly Associated With 25OHD Blood Vitamin D Level | AT BASELINE | RECTAL MUCOSA GENE EXPRESSION (HT12 microarray. No units on gene expression array) |
| GENE EXPRESSION CHANGE | AFTER 12 WEEK'S SUPPLEMENTATION | RECTAL MUCOSA GENE EXPRESSION. We tested supplemented patients (i.e. response to supplementation) for enrichment of the candidate gene-set. Directional gene-set testing was performed in R, using the gene-setTest function in the 'limma' package. We performed participant-level gene-set enrichment testing with a 'response' to supplementation defined as enrichment (P\<0.001) of the candidate gene-set after supplementation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| VITAMIN D STATUS | AT BASELINE | Blood vitamin D level (25-hydroxy-vitamin D (25-OHD) level (nmol/l)) using Liquid chromatography tandem mass spectrometry (LC- MS/MS) |
| VITAMIN D STATUS CHANGE | AFTER 12 WEEK'S SUPPLEMENTATION | Blood vitamin D level (25-hydroxy-vitamin D (25-OHD) level (nmol/l)) |
Countries
United Kingdom
Participant flow
Pre-assignment details
Analyses were intended to be conducted irrespective of previous diagnosis status. i.e. Results are not compared between those with/ without previous history of colorectal cancer.
Participants by arm
| Arm | Count |
|---|---|
| INTERVENTION STUDY TREATED WITH 3200IU FULTIUM VITAMIN D3
FULTIUM D3 VITAMIN D3: VITAMIN D3 SUPPLEMENT | 50 |
| Total | 50 |
Baseline characteristics
| Characteristic | INTERVENTION STUDY | — |
|---|---|---|
| Age, Continuous | 66 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 24 Participants | — |
| Sex: Female, Male Male | 26 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 50 |
| serious Total, serious adverse events | 0 / 50 |
Outcome results
Primary
GENE EXPRESSION CHANGE
RECTAL MUCOSA GENE EXPRESSION. We tested supplemented patients (i.e. response to supplementation) for enrichment of the candidate gene-set. Directional gene-set testing was performed in R, using the gene-setTest function in the 'limma' package. We performed participant-level gene-set enrichment testing with a 'response' to supplementation defined as enrichment (P\<0.001) of the candidate gene-set after supplementation.
Time frame: AFTER 12 WEEK'S SUPPLEMENTATION
Population: Recruited patients were those both with and without previous history of cancer. However, analyses were intended to be conducted irrespective of previous diagnosis status. i.e. Results are not compared between those with/ without previous history of colorectal cancer.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| INTERVENTION STUDY | GENE EXPRESSION CHANGE | 9 Participants |
Primary
Number of Genes Significantly Associated With 25OHD Blood Vitamin D Level
RECTAL MUCOSA GENE EXPRESSION (HT12 microarray. No units on gene expression array)
Time frame: AT BASELINE
Population: Recruited patients were those both with and without previous history of cancer. However, analyses were intended to be conducted irrespective of previous diagnosis status. i.e. Results are not compared between those with/ without previous history of colorectal cancer.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| INTERVENTION STUDY | Number of Genes Significantly Associated With 25OHD Blood Vitamin D Level | 629 significant probes (P<0.01) |
Secondary
VITAMIN D STATUS
Blood vitamin D level (25-hydroxy-vitamin D (25-OHD) level (nmol/l)) using Liquid chromatography tandem mass spectrometry (LC- MS/MS)
Time frame: AT BASELINE
Population: Fifty subjects were administered 3200IU/day oral vitamin D3 and matched blood/mucosa resampled after 12 weeks'. Analyses were intended to be conducted irrespective of previous diagnosis status. i.e. Results are not compared between those with/ without previous history of colorectal cancer.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| INTERVENTION STUDY | VITAMIN D STATUS | 40 nmol/l |
Secondary
VITAMIN D STATUS CHANGE
Blood vitamin D level (25-hydroxy-vitamin D (25-OHD) level (nmol/l))
Time frame: AFTER 12 WEEK'S SUPPLEMENTATION
Population: Recruited patients were those both with and without previous history of cancer. However, analyses were intended to be conducted irrespective of previous diagnosis status. i.e. Results are not compared between those with/ without previous history of colorectal cancer.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| INTERVENTION STUDY | VITAMIN D STATUS CHANGE | Vitamin D Level at Baseline | 35.85 nmol/l |
| INTERVENTION STUDY | VITAMIN D STATUS CHANGE | Vitamin D Level at 12 weeks | 89 nmol/l |