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

Table 3 Characteristics of the six case-control 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	Age (yr)	No. cases (M/W), endpoint	No. controls and type	Gene (SNP)	CIMP markers	MSI	Nutrient/alcohol	Method for measuring nutrition intake	Outcome (OR, 95%CI), interaction			NOS
										CIMP markers/MSI–nutrient/alcohol	CIMP markers-/MSI–SNP–nutrient/alcohol	Adjustments to OR
Busch et al[31]	United States	40-80 (AAs vs EAs)	244/241 CRC	Analyses were only performed in tumour tissue		CACNA1G, hMLH1, NEUROG1, RUNX3, SOCS1	Unk	Dietary folate and alcohol	Unk	EAs: High CACNA1G methylation tumour (cut point of 5%)–high folate intake: 0.3 (0.14-0.66); high SOCS1 methylation tumour (cut point of 3%)–high folate intake: 0.3 (0.11-0.80)	Unk	-	4
Curtin et al[32]	United States	30-79	518/398 CCa	1972 C	MTHFR (677C>T, 1298A>C), TS variants (TSER, TTAAAG in 3´-UTRs 1494), MTR (919D>G), RFC (80G>A), MTHFD1 (R134K, R653Q), ADH3 (1045A>G)	MINT1, MINT2, MINT31, p16, hMLH1	Unk	Dietary folate, Met, vitamin B12, and alcohol	Adaptation of the CARDIA diet history	Unk	MTHFR 1298AA–alcohol (high vs none): CIMP+, 0.5 (0.3-0.97), P < 0.01; ADH3 (1 or 2 variant, slow catabolizing*2 vs homozygous for the common allele)–folate (low): CIMP+, 1.6 (1.03-2.6), P = 0.02. MTHFR 1298AC or CC-high-risk dietary pattern (low in folate or Met intake, high in alcohol): CIMP+, 2.1 (1.3-3.4), P = 0.03	Age, centre, other SNPs, sex, smoking intensity, and race	9
Curtin et al[33]	United States	30-79	559/392	1205 C	MTHFR (1298A>C), TP53, KRAS2,	CDKN2A, hMLH1, MINT 1, 2 and 31		Folate, riboflavin, vitamins B6, B12, and Met	Adaptation of the CARDIA diet history (by interview)	M: Folate (T3 vs T1)–CIMP+, 3.2 (1.5-6.7), P < 0.01	1298 AC/CC (vs AA)–folate (T3 vs T1): 0.4 (0.2-1.0), P = 0.04, for CIMP+	Age, centre, intake of energy and fibre, NSAID use, oestrogen use (W), PA, race, referent year, sex, screening, and smoking	8
Kim et al[34]	Korea	30-79	465/322 CRC (363 CCa, 330 RCa)	656 H	MTHFR (677C>T)	Unk	2 mononucleotide markers (Bat25 and Bat26) and 3 dinucleotide markers (D2S123, D5S346, and D17S250)	Folate, vitamins B2, B6, B12, niacin, Met, and choline	Validated FFQ	Unk	DCCa: hMSH3 (rs41097) AG/GG (vs AA)–niacin (> 14.00 mg/d vs < 14.00 mg/d)–MSI–MMR status: 0.49 (0.28-0.84), P-interac = 0.008	Age, intake of energy and alcohol, BMI, CRC family history, educational level, occupation, income, PA, sex, and smoking status	7
Slattery et al[35]	United States	30-79	821/689 CRC	2410 C	Unk	Unk	10 tetranucleotide repeats, 3 Bat-26 and TGFbRII	Dietary folate, and alcohol	Validated CARDIA diet questionnaire	Alcohol–MSI+ (vs MSI-): 1.6 (1.0-2.5), P-trend = 0.03; liquor–MSI+ (vs MSI-): 1.6 (1.1-2.4), P-trend = 0.02		Age, BMI, intake of energy, fibre and calcium, intake, PA, sex	7
Slattery et al[36]	United States	30-79	638/516 CRC	2410 C	BRAF (V600E)	MINT1, MINT2, MINT31, p16 and hMLH1	Unk	Folate, vitamins B6 and B12, Met, and alcohol	Diet history questionnaire	No assoc	MSI tumour–alcohol (high vs none): 1.6 (0.9-2.9), P-trend = 0.04, for p16 unmethylated; 1.7 (0.7-4.3), P-trend = 0.06, for CIMPlow (< 2 markers); 2.2 (1.2-3.7), P-trend = 0.01, for BRAF wildtype	Age, alcohol intake, BMI, intake of energy and folate, density of calcium and fibre, NSAIDs use, PA, sex, smoking intensity	7

AA: African Americans; ADH3: Alcohol dehydrogenase 3; 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; C: community controls; CACNA1G: Calcium voltage-gated channel subunit a1 G; CCa: Colon cancer; CDKN2A: Cyclin-dependent kinase inhibitor 2A; CI: Confidence interval; CIMP: CpG island methylator phenotype; CRC: Colorectal cancer; EA: European Americans; FFQ: Food frequency questionnaire; H: Hospital controls; hMLH1: Human MutL homolog 1; hMSH3: Human MutS homolog 3; interact: Interaction; KRAS: Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; M: Men; Met: Methionine; MINT: Methylated in tumours; MMR: Mismatch repair; MSI: Microsatellite instability; MTHFD: Metilentetrahidrofolate dehydrogenase; MTHFR: Methylenetetrahydrofolate reductase; MTR: Methionine synthase; NEUROG1: Neurogenin1; NOS: Quality Newcastle-Ottawa Scale; NSAID: Nonsteroidal anti-inflammatory drugs; OR: Odds ratio; PA: Physical activity; RCa: Rectal cancer; RFC: Reduced folate carrier; RUNX3: Runt-related transcription factor 3; SNP: Single-nucleotide polymorphism; SOCS1: Suppressor of cytokine signalling 1; T: Tertile; TGFbRII: Transforming growth factor β receptor type II; TS: Thymidylate synthase; TSER: Thymidylate synthase enhancer region; TP53: Tumour protein p53; unk: Unknown; UTR: Untranslated region; W: Women.