Genomics|HuGENet|Reviews|Table|Folate Metabolism and Colorectal Neoplasia|PubMed ID: 14977639

Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review
Linda Sharp and Julian Little

Tables

TABLE 1: Environmental factors associated with colorectal cancer

Increasing risk	Reducing risk
Excess weight*	Physical activity†

Tobacco smoking‡	Hormone replacement therapy §

Alcohol¶	Aspirin and other nonsteroidal anti-inflammatory drugs#
	Vegetables**

* Bergström et al. (117); International Agency for Research on Cancer (IARC) Working Group (118).
† IARC Working Group (118).
‡ Giovannucci (119).
§ Beral et al. (121); Rossouw et al. (122).
¶ World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) (120); Cotton et al. (109): results of studies are heterogeneous.
# IARC Working Group (123).
** WCRF/AICR (120); Terry et al. (124); Flood et al. (125): results of studies are heterogeneous.

TABLE 2: Studies of the MTHFR * C677T genotype and colorectal carcinoma, with relative risks and 95% confidence intervals

Study area	Cases		Comparison group				Com-parison	Rela-tive risk	95% CI*	Adjust-ment factors	Re-ference no.
Study area	Type	No.	Type	No.	% TT	95% CI	Com-parison	Rela-tive risk	95% CI*	Adjust-ment factors	Re-ference no.
Australia†	Patients undergoing surgery for colorectal cancer at a hospital in Western Australia during 1985–1998; Duke’s stage B or C; 46% male; 48% aged <70 years	501	"Healthy" persons from Western Australia; aged 20–92 years; 81% aged <70 years	1,207	11.0	8.4, 14.0	TT vs. CC	1.03‡	0.71, 1.49		98
							CT vs. CC	0.75‡	0.60, 0.95
Korea	Patients undergoing an operation for colorectal cancer at two centers; 51% male	200	"Healthy" unrelated adults without colorectal cancer; source not stated.	460	16.1	12.8, 19.8	TT vs. CC	0.81‡	0.46, 1.42		151
							CT vs. CC	0.94‡	0.64, 1.39
Mexico†	Patients with colorectal cancer	74	"Asymp-tomatic" subjects; source not stated	110	21.8	14.5, 30.7	TT vs. CC	1.61‡	0.62, 4.19		152
							CT vs. CC	1.83‡	0.84, 4.11
United Kingdom: Scotland	Residents of Grampian who had a first primary, histologically confirmed, colorectal cancer diagnosed in 1998–2000; 57% male; median age, 70 years	251	Persons randomly selected from lists of all those registered with general practitioners in Grampian; frequency matched to cases on age and sex; 51% male; median age, 62 years	394	11.9	8.9, 15.5	TT vs. CC	0.93	0.66, 1.32	Age, sex	56, 153
							CT vs. CC	0.72	0.41, 1.28
United Kingdom: Perth, Dundee, Leeds, York	Patients with incident colorectal cancer from four hospitals; aged 45–80 years; Caucasian; no history of familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, diverticular disease, or previous malignancy	490	Controls from general practices; no history of previous cancer	592	8.3	6.2, 10.8	TT vs. CC	1.23	0.81, 1.88		155
							CT vs. CC	0.83	0.65, 1.07
United States	Men enrolled in the Health Professionals Follow-up Study in 1986 who provided a blood sample in 1993–1994; self-reported colorectal cancer, confirmed from medical records and diagnosed in 1986–1994; aged 40–75 years at enrollment in 1986; cohort predom-inantly White	144	Male controls selected from the same cohort from among those who provided a blood sample in 1993–1994 but who did not report a diagnosis of colorectal cancer	627	13.4	10.8, 16.3	TT vs. CT/CC	0.57	0.30, 1.06	Age, family history, and intake of folate, methionine, and alcohol	149
United States	Male physicians participating in Physicians Health Study trial (exclusion criteria included history of myocardial infarction, stroke or ischemic heart disease, cancer, current renal or liver disease, peptic ulcer, or gout) who provided a blood sample at baseline in 1982 and reported colorectal cancer in 1982–1985, which was confirmed in medical records; mean age, 60 (standard deviation, 9) years	202	Male controls selected from the same cohort, matched to cases on age and smoking status; alive and free of colorectal cancer when matched case was diagnosed; mean age, 57 (standard deviation, 8) years	326	15.0	11.3, 19.4	TT vs. CC	0.45	0.24, 0.86	Age, smoking status, alcohol intake, multivitamin use, exercise, body mass index, aspirin use	17
							CT vs. CC	0.98	0.67, 1.45
United States: North Carolina	Persons with first invasive colon adeno-carcinoma diagnosed in July 1996–June 2000, identified from cancer registry, aged 40–85 years at diagnosis, and had driver’s license if under age 65 years; response rate, 66%; 52% male; 44% reported being African-American, 56% as White	552	Controls selected from 1) motor vehicle records (under age 65 years) or 2) lists of Medicare-eligible beneficiaries (aged >=65 years); frequency matched to cases on ethnic group, age, sex; 38% African American, 62% White	868	6.6§	5.0, 8.4	TT vs. CC	0.8	0.5, 1.4	Age, ethnic group, sex, sampling fractions	154
							CT vs. CC	1.1	0.9, 1.4
United States: Utah and Minn-esota	Participants in KPMCP* and residents of eight counties of Utah and Twin Cities area of Minnesota diagnosed with first primary colon cancer in 1991–1994; aged 30–74 years at diagnosis; 56% male; ethnic group of entire study population 4.2% Black, 4.4% Hispanic, 91.4% White; 75% of cases and controls genotyped	1,467	Controls 1) randomly selected from KPMCP lists, and 2) identified by random digit dialing and lists with driver’s license or state identification in Minnesota and Utah (under age 65 years) and 3) randomly selected from Medical Care Financing lists in Utah (aged >=65 years)	1,821	11.4	9.9, 12.9	TT vs. CC	0.9	0.7, 1.1	Age, body mass index, long-term vigorous physical activity, energy intake, dietary fiber, usual no. of cigarettes smoked	150
							CT vs. CC	1.0	0.9, 1.2
United States: Hawaii	Persons with primary adeno-carcinoma of the colon or rectum diagnosed in 1994–1998; identified through tumor registry; at least 75% Japanese or Caucasian or any percentage Hawaiian ancestry; 61% male; median age, 66 years; 59% Japanese, 27% Caucasian, 14% Hawaiian	548	Controls selected from 1) participants in an ongoing health survey among a 2% random sample of state households and 2) for those over age 65 years, Health Care Financing Administration rolls; 61% Japanese, 26% Caucasian, 13% Hawaiian	656	15.9¶	13.1, 18.9	TT vs. CC	0.7	0.5, 1.0	Age, sex, ethnicity, smoking, physical activity, aspirin use, body mass index, schooling, intakes of nonstarch poly-saccharides and calcium	54
							CT vs. CC	0.8	0.6, 1.1

* MTHFR, methylenetetrahydrofolate reductase; CI, confidence interval; KPMCP, Kaiser Permanente Medical Care Program.
† DNA source: tumor for cases, blood for controls.
‡ Unmatched odds ratio, computed by Sharp and Little from data in the paper.
§ %TT: African Americans = 1.8 (95% CI: 0.7, 3.9); Whites = 9.5 (95% CI: 7.1, 12.3).
¶ %TT: Japanese = 19.4 (95% CI: 15.6, 23.6); Caucasian = 14.0 (95% CI: 9.2, 20.2); Hawaiian = 3.4 (95% CI: 0.9, 9.6).

TABLE 3: Studies of the MTHFR * C677T genotype and adenomatous polyps, with relative risks and 95% confidence intervals

Study area	Cases		Comparison group			Compar-ison	Rela-tive risk	95% CI*	Adjustment factors	Ref-erence no.
Study area	Type	No.	No.	% TT	95% CI	Compar-ison	Rela-tive risk	95% CI*	Adjustment factors	Ref-erence no.
United States	Women enrolled in the Nurses’ Health Study in 1976 who provided a blood sample in 1989–1990; first incident proximal or distal colorectal adenoma diagnosed during time from blood specimen to June 1994; approximately 95% of the cohort is White	257	713	9.3	7.2, 11.6	TT vs. CT/CC	1.35	0.84, 21.7	Age, family history, smoking status, body mass index, and intakes of folate, methionine, alcohol, fiber, and saturated fat	76
United States: California	Subjects undergoing screening sigmoidoscopy at two medical centers during 1991–1993; aged 50–74 years; no evidence of prior bowel disease and no previous bowel surgery									160
	Diagnosed for the first time with one or more histologically confirmed adenomas; 65% male; 55% White, 17% Black, 17% Hispanic, 11% Asian; mean age, 67 years	471	510	9.6	7.2, 12.5	TT vs. CC	1.11	0.71, 1.71	Age, race, sex, clinic, date of sigmoidoscopy
						CT vs. CC	0.85	0.65, 1.13
United States: Minnea-polis, Minnesota	Subjects recruited from private gastroenterology practice undertaking colonoscopies in 10 hospitals; underwent colonoscopy in 1991–1994; English speaking; no known genetic syndromes predisposing to colorectal cancer; no history of cancer or inflammatory bowel disease; aged 30–74 years; participation rate, 68%									159
	Subjects with first diagnosis of colon or rectal adenomas; 62% male; mean age, 58.1 (standard deviation, 9.7) years; 98% White	527	645	11.0	8.7, 13.7	TT vs. CC	0.8	0.5, 1.3	Age, sex, body mass index, use of hormone replacement therapy, and percentage of calories from fat, dietary fiber, folate, vitamin B₁₂, vitamin B₆, methionine, alcohol
						CT vs. CC	0.9	0.7, 1.2
Japan	Male military officials undergoing preretirement health examination at two hospitals; had a partial or total colonoscopy and provided a blood sample; aged 47–55 years; no prior history of colectomy, polypectomy, malignant neoplasia									161
	Histologically confirmed colorectal adenoma without in situ or invasive carcinoma	205	220	11.8	7.9, 16.8	TT vs. CC	0.87	0.56, 1.34	Hospital, employment, military rank, smoking, alcohol intake
						CT vs. CC	1.17	0.61, 2.23
Norway	Participants in Telemark I study; born in 1924–1933; selected from population register in 1983 and randomly assigned to endoscopy or control group; 799 participated; in 1996, offered colonoscopy and removal of polyps; results available for 443 participants (229 male, 214 female; median age, 67 years)									162
	Subjects with "high-risk" colorectal adenomas (>=10 mm or severe dysplasia or villous components)	47	394	7.1	4.8, 10.1	TT vs. CC	2.41	0.82, 7.06	Age, sex, red blood cell folate, use of nonsteroidal antiinflammatory drugs, flexible sigmoidoscopy in 1983, body mass index, current smoking
						CT vs. CC	1.51	0.76, 2.99
Mexico	Patients with colorectal adenomas	32	110	21.8	14.5, 30.7	TT vs. CC	1.65†	0.41, 6.73		152
						CT vs. CC	0.98†	0.28, 3.67

* MTHFR, methylenetetrahydrofolate reductase; CI, confidence interval.
† Unmatched odds ratio, computed by Sharp and Little from data in the paper.

TABLE 4: Studies of the MTHFR * C677T genotype and hyperplastic polyps, with relative risks and 95% confidence intervals

Study area

Cases

Comparison group

Compar-ison

Relative risk

95% CI*

Adjust-ment factors

Ref-erence no.

Type

No.

Type

No.

% TT

95% CI

Norway

Participants in Telemark I study; born 1924–1933; selected from population register in 1983 and randomly assigned to endoscopy or control group; 799 participated; in 1996, offered colonoscopy and removal of polyps; results available for 443 participants (229 male, 214 female; median age, 67 years)

162

With "high-risk" hyperplastic polyps (n >= 3)

Without polyps (n = 116) or with adenomas or "low-risk" hyperplastic polyps (n = 233)

349

7.1

4.8, 10.1

TT/CT vs. CC

1.43†

0.87, 2.33

United States: Minnea-polis, Minnesota

Subjects recruited from private gastroenterology practice undertaking colonoscopies in 10 hospitals; underwent colonoscopy in 1991–1994; English speaking; without known genetic syndromes predisposing to colorectal cancer; no history of cancer or inflammatory bowel disease; aged 30–74 years

163

Diagnosis of colon or rectal hyperplastic polyps; 97% White; 57% male; mean age, 53.7 years

200

Free of all polyps at colonoscopy; 97% White; 38% male; mean age, 52.8 (standard deviation, 10.9) years

645

11.0

8.7, 13.7

TT vs. CC

0.9

0.5, 1.6

Age, sex, body mass index, use of hormone replace-ment therapy, smoking, percentage of calories from fat, dietary fiber, folate, vitamin B₁₂, vitamin B₆, methionine, alcohol

CT vs. CC

0.8

0.6, 1.2

* MTHFR, methylenetetrahydrofolate reductase; CI, confidence interval.

† Unmatched odds ratio, computed by Sharp and Little from data in the paper.

TABLE 5: Studies of the MTHFR * A1928C polymorphism, other folate pathway genes, and colorectal neoplasia

Gene	Poly-morphism	Study area, study design, cases†	Gene-disease associations			Gene-environment interaction	Gene-gene inter-actions	Ref-erence no.
Gene	Poly-morphism	Study area, study design, cases†	Comparison	Relative risk	95% CI*	Gene-environment interaction	Gene-gene inter-actions	Ref-erence no.
MTHFR	A1298C	United States, case-control, carci-noma	CC vs. AA	0.8	0.5, 1.4	No interactions with total or dietary folate, vitamin B₆, vitamin B₁₂, riboflavin, methionine, ethanol‡		54
		United States, nested case-control, carci-noma	CC vs. AA	0.73	0.37, 1.43	Risk associated with CC not modified by plasma folate status‡		17, 28
		United States, case-control, carci-noma	CC vs. AA	0.6	0.4, 0.9	Significant interaction between A1298C and total folate intake for Whites only; among African Americans, combined C677T and A1298C genotype and total folate produced interaction of borderline significance; no significant interactions of A1298C and alcohol intake for either ethnic group		154
		Scotland, case-control, carcinoma	CC vs. AA	0.67	0.39, 1.13	—§		56
MTR*	A2756G	United States, nested case-control, adenoma	GG vs. AA	0.66	0.26, 1.70	—§	No significant interaction with MTHFR C677T‡	76
		United States, case-control, carcinoma	GG vs. AA	1.1	0.6, 2.2	No interactions with total or dietary folate, vitamin B₆, vitamin B₁₂, riboflavin, methionine, ethanol‡	Significant interaction with MTHFR C677T	54
		United States, nested case-control, carcinoma	GG vs. AA	0.59	0.27, 1.27	Significant interaction with alcohol; suggestion of possible joint effect with plasma folate, but not significant; no interaction with homocysteine; no significant interaction with vitamin B₁₂‡	—§	18
MTRR*	A66G	United States, case-control, carcinoma	GG vs. AA	1.4	0.9, 2.0	No interactions with total or dietary folate, vitamin B₆, vitamin B₁₂, riboflavin, methionine, ethanol‡	No interaction with MTHFR C677T	54
CBS*	68 bp* insertion	United States, case-control, carcinoma	Weak inverse association with presence of insertion¶			No interactions with total or dietary folate, vitamin B₆, vitamin B₁₂, riboflavin, methionine, ethanol‡	Weak suggestion of possible interaction with MTHFR C677T	54
		Australia, case-control, carcinoma#	Frequency of heterozygotes in controls (10%) vs. cases (5%)			—‡‡		98
TS*	28 bp tandem repeat	United States, case-control, adenoma	2 rpt*/2 rpt vs.	0.9	0.6, 1.3	Significant interaction with total folate intake; borderline significant interaction with total vitamin B₁₂ intake	Suggestion of joint effect with MTHFR C677T	102
			3 rpt/3 rpt			No interactions with vitamin B₆, methionine, or alcohol‡
	28 bp tandem repeat	United States, case-control, carcinoma	2 rpt/2 rpt vs. 3 rpt/3 rpt	0.65	0.38, 1.12			99
	6 bp deletion in 3' untranslated region	United States, case-control, carcinoma	With deletion vs. no deletion	1.40	0.99, 1.98			164
	6 bp deletion in 3' untranslated region	United States, case-control, adenoma	Homozygous no deletion vs. 6 bp/6 bp	1.13	0.73, 1.74	No consistent patterns with dietary folate or vitamin B₁₂ ‡	No consistent patterns with MTHFR C677T‡	102

* MTHFR, methylenetetrahydrofolate reductase; CI, confidence interval.

† Unmatched odds ratio, computed by Sharp and Little from data in the paper.

TABLE 6: Research priorities

1.
Further documentation of genotype frequencies: large, population-based studies of the polymorphisms reported in this paper and the additional, but less well studied, polymorphisms in these genes (e.g., G1793A in MTHFR ), including prevalences of combinations of polymorphisms and prevalence in different age groups; particularly needed in non-White populations and less-investigated ethnic groups in the United States and Europe

2.
Clarification of functional effects of the polymorphisms: including exploration of 1) consequences of carrying combinations of polymorphisms in both in vivo and in vitro systems and 2) in vivo functional effects of particular genotypes in persons with different levels of intake of folate and related dietary factors

3.
Further investigation of hypothesized mechanisms: examination of whether the polymorphisms are associated, in humans, with genomic DNA methylation, uracil incorporation, or DNA strand breaks, including exploration of whether relations differ according to levels of folate and related dietary factors

4.
Studies of gene-disease associations and gene-environment and gene-gene interactions: further large population-based studies of polymorphisms and cancer and adenomas, incorporating collection of high-quality dietary data and, ideally, blood biomarkers; these studies should be large enough to have sufficient power to investigate gene-environment and gene-gene interactions and to undertake subgroup analysis by age and ethnic group, of colon and rectal tumors, proximal and distal tumors, and tumors with microsatellite instability or loss of heterozygosity.

5.
Pooled analyses of studies of gene-disease associations and gene-environment and gene-gene interactions to facilitate subgroup analyses and investigation of interactions.

6.
Investigation of the role of other folate pathway genes, and interactions with alcohol-metabolizing genes, in the etiology of colorectal neoplasia.

7.
Investigation of genotype in adenomatous polyps: including 1) association with risk of recurrence and 2) association with particular pathologic features and 3) incorporation of genotyping in randomized controlled trials of folate supplementation in prevention of colorectal neoplasia.

8.
Further investigation of genotype and quality of life and the effectiveness of treatment in patients with colorectal cancers: large studies of representative groups of patients; analysis should include adjustment for known prognostic factors.

9. Development of methodology for specifying hypotheses and statistical analysis in the context of interactions between multiple genes and multiple environmental factors.

Page last reviewed: March 1, 2004 (archived document)
Page last updated: November 2, 2007
Content Source: CDC's Office of Public Health Genomics