Influence of methyl donor nutrients as epigenetic regulators in colorectal cancer: A systematic review of observational studies

Table 4 Characteristics of the five cohort studies included in this systematic review examining the interactive effects between single-nucleotide polymorphisms in genes encoding methyl-metabolizing enzymes and/or mutations in oncogenes, CpG island methylator phenotype and/or microsatellite instability, and one-carbon metabolism-related dietary compounds on colorectal cancer risk

Ref.	Country	Study cohort (age, yr)	No. participants (M/W)	No. incident cases	Follow-up length, yr	Gene (SNP)	CIMP markers	MSI	Nutrient/alcohol	Method for measuring nutrition intake	Outcome (RR, 95%CI) interaction			NOS
											CIMP markers/MSI–nutrient/alcohol	CIMP markers–/MSI–SNP–nutrient/alcohol	Adjustments to RR
de Vogel et al[9]	Netherlands	The Netherlands Cohort Study on diet and cancer (55-69)	58279/62573	734 CRC	7.3	MTHFR (rs1801133, rs1801131), MTR (rs1805087), MTRR (rs1801394), DNMT3B (rs2424913, rs406193), EHMT1 (rs4634736), EHMT2 (rs535586), PRDM2 (rs2235515)	CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1	Bat-26, Bat-25, NR-21, NR-22, NR-24	Dietary folate, Met, vitamins B2 and B6, alcohol	Validated FFQ (self-reported)	No assoc	Unk	BMI, CRC family history, intake of energy and alcohol, sex, and smoking status	9
de Vogel et al[37]	Netherlands	The Netherlands Cohort Study on diet and cancer (55-69)	58279/62573	734 CRC	7.3	BRAF (V600E)			Dietary folate, Met, vitamins B2 and B6, alcohol	Validated FFQ (self-reported)	M: BRAF mut–folate (T3 vs T1): 3.04 (1.13-8.20), P-trend = 0.03; BRAF mut–Met (T3 vs T1): 0.28 (0.09-0.86), P-trend = 0.02); hMLH1 hypermethylation–vitamin B6 (T3 vs T1): 3.23 (1.15-9.06), P- trend = 0.03	Unk	Age, BMI, CRC family history, intake of energy, meat, total fat, fibre, vitamin C, total iron and calcium, smoking status	9
Schernhammer et al[38]	United States	The Nurses' Health Study (W) (30-55) and the Health Professional Follow-up Study (M) (40–75)	47371/88691	669 CCa	22	KRAS	Unk	D2S123, D5S346, D17S250, Bat25, Bat26 (14), Bat40, D18S55, D18S56, D18S67, D18S487	Folate, vitamins B6 and B12, Met, and alcohol	Validated FFQ (self-reported)	Unk	MSI/KRAS–folate: No assoc for CCa. MSI/KRAS–vitamins B6 or B12: No assoc for CCa	Age, aspirin use, smoking, BMI, colon polyps, CRC family history, intake of alcohol, energy, beef, calcium, vitamins B6 and B12, and Met, multivitamin use, PA, sex, screening sigmoidoscopy	9
Schernhammer et al[39]	United States	The Nurses’ Health Study (30- 55)	88691 W	375 CCa		BRAF	CHFR, MGMT, p14, WRN, HTC1, MINT1, MINT31, IGFBP3	Unk			Folate (Q4 vs Q1: No assoc with CIMP–high tumour risk; and no assoc with BRAF status	Unk
van Engeland et al[40]	Netherlands	Netherlands Cohort Study on Diet and Cancer (55-69)	58279/62573	122 CRC	7.3	Unk	APC-1A, p14ARF, p16INK4A, hMLH1, O6-MGMT, and RASSF1A	Unk	Dietary folate and alcohol	Validated FFQ (self-reported)	Low vs high-methyl donor intake–promoter methylation (> 1 gene methylated): No assoc	Unk	Age, CRC family history, intake of energy, fibre, vitamin C, and iron, sex	9

APC: Adenomatous polyposis coli; asso: Significant association; Bat: Mononucleotide microsatellite with quasi-monomorphic allele length distribution in healthy controls but unstable; BMI: Body mass index; BRAF: B-Raf proto-oncogene; CACNA1G: Calcium voltage-gated channel subunit a1 G; CCa: Colon cancer; CHFR: RING finger domain protein; CI: Confidence interval; CIMP: CpG island methylator phenotype; CRC: Colorectal cancer; DNMT3B: DNA methyltransferase 3 EHMT: Euchromatin histone methyltransferase; FFQ: Food frequency questionnaire; hMLH1: Human MutL homolog 1; HTC: Histidine triad with channel; IGF2: Insulin-like growth factor 2; IGFBP: Insulin-like growth factor-binding protein; KRAS: Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; M: Men; Met: Methionine; MGMT: DNA repair enzyme O(6)-methylguanine-DNA methyltransferase; MINT: Methylated in tumours; MSI: Microsatellite instability; MTHFR: Methylenetetrahydrofolate reductase; MTR: Methionine synthase; MTRR: Methionine synthase reductase; mut: Mutation; NEUROG1: Neurogenin1; NOS: Quality Newcastle-Ottawa Scale; PA: Physical activity; PRDM2: PR domain zinc finger protein 2; Q: Quartile; RASSF1A: Ras association domain family 1 isoform A; RR: Relative risk; RUNX3: Runt-related transcription factor 3; SNP: Single-nucleotide polymorphism; SOCS1: Suppressor of cytokine signalling 1; T: Tertile; unk: Unknown; W: Women; WRN: Werner syndrome gene.