MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan

doi:10.3748/wjg.v27.i34.5737

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World Journal of Gastroenterology

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Retrospective Cohort Study

World J Gastroenterol. Sep 14, 2021; 27(34): 5737-5752
Published online Sep 14, 2021. doi: 10.3748/wjg.v27.i34.5737

Table 1 Primer sequences, annealing temperature and product size for methylation-specific polymerase of target genes

Genes		Forward primer (5’→3’)	Annealing temperature (oC)	Product size (bp)
CDKN2A	M	F: TTATTAGAGGGTGGGGCGGATCGC	62	150
	M	R: GACCCCGAACCGCGACCGTAA	62	150
	U	F: TTATTAGAGGGTGGGGTGGATTGT	62	151
	U	R: CAACCCCAAACCACAACCATAA	62	151
MLH1	M	F: ACGTAGACGTTTTATTAGGGTCGC	60	118
	M	R: CCTCATCGTAACTACCCGCG	60	118
	U	F: TTTTGATGTAGATGTTTTATTAGGGTTGT	60	124
	U	R: ACCACCTCATCATAACTACCCACA	60	124
MGMT	M	F: TTTCGACGTTCGTAGGTTTTCGC	53	81
	M	R: GCACTCTTCCGAAAACGAAACG	53	81
	U	F: TTTGTGTTTTGATGTTTGTAGGTTTTTGT	53	93
	U	R: AACTCCACACTCTTCCAAAAACAAAACA	53	93

MSP: Methylation-specific polymerase chain reaction; M: Methylation; U: Unmethylation.

Table 2 Clinical characteristics of colorectal cancer patients and MTNR1B genotypes (rs1387153 and rs2166706)

No of subjects	Total	rs1387153 (C>T)						rs2166706 (T>C)
No of subjects	Total	CC (%)	CT (%)	TT (%)	P value	CC + CT (%)	P value	TT (%)	TC (%)	CC (%)	P value	TT + TC (%)	P value
Sex
Male	39 (41.5)	8 (34.8)	20 (41.7)	10 (47.6)	0.69	28 (39.4)	0.62	8 (36.4)	20 (40.8)	11 (47.8)	0.73	28 (39.4)	0.63
Female	55 (58.5)	15 (65.2)	28 (58.3)	11 (52.4)		43 (60.6)		14 (63.6)	29 (59.2)	12 (52.2)		43 (60.6)
Age at surgery
mean ± SD (yr)	64.2 ± 13.8	66.8 ± 13.8	61.7 ± 13.8	67.0 ± 13.3	0.20	63.3 ± 13.9	0.29	67.4 ± 13.8	61.8 ± 13.8	65.6 ± 13.5	0.24	63.6 ± 13.9	0.54
< 65	50 (53.2)	12 (52.2)	27 (56.2)	10 (47.6)	0.80	39 (54.9)	0.62	11 (50.0)	27 (55.1)	12 (52.2)	0.92	38 (53.5)	1.00
≥ 65	44 (46.8)	11 (47.8)	21 (43.8)	11 (52.4)		32 (45.1)		11 (50.0)	22 (44.9)	11 (47.8)		33 (46.5)
Stage
I	12 (12.8)	2 (8.7)	6 (12.5)	4 (19.0)	0.31	8 (11.3)	0.12	2 (9.1)	6.1 (2.2)	4 (17.4)	0.24	8 (11.3)	0.08
II	34 (36.2)	9 (39.1)	18 (37.5)	6 (28.6)		27 (38.0)		8 (36.4)	19 (38.8)	7 (30.4)		27 (38.0)
III	30 (31.9)	10 (43.5)	16 (33.3)	4 (19.0)		26 (36.6)		10 (45.5)	16 (32.7)	4 (17.4)		26 (36.6)
IV	18 (19.1)	2 (8.7)	8 (16.7)	7 (33.3)		10 (14.1)		2 (9.1)	8 (16.3)	8 (34.8)		10 (14.1)
Adjuvant chemotherapy^a
No	23 (24.5)	5 (22.7)	12 (25.5)	6 (33.3)	0.74	17 (24.6)	0.55	5 (23.8)	12 (25.5)	6 (30.0)	0.90	17 (25.0)	0.77
Yes	65 (69.1)	17 (77.3)	35 (74.5)	12 (66.7)		52 (75.4)		16 (76.2)	35 (74.5)	4 (70.0)		51 (75.0)
Tumor location^a
Colon	74 (78.7)	21 (95.5)	41 (87.2)	11 (61.1)	< 0.001	62 (89.9)	< 0.001	20 (95.2)	41 (87.2)	13 (65.0)	0.02	61 (89.7)	0.01
Rectum	14 (14.9)	1 (4.5)	6 (12.5)	7 (38.9)		7 (10.1)		1 (4.8)	6 (12.8)	7 (35.0)		7 (10.3)
CDKN2A gene
Unmethylation	43 (45.7)	13 (56.5)	19 (39.6)	10 (47.6)	0.40	32 (45.1)	1.00	12 (54.5)	21 (42.9)	10 (43.5)	0.64	33 (46.5)	0.99
Methylation	51 (54.3)	10 (43.5)	29 (60.4)	11 (52.4)		39 (54.9)		10 (45.5)	28 (57.1)	13 (56.5)		38 (53.5)
MLH1 gene
Unmethylation	77 (81.9)	20 (87.0)	38 (79.2)	17 (81.0)	0.73	58 (81.7)	1.00	19 (86.4)	39 (79.6)	19 (82.6)	0.79	58 (81.7)	1.00
Methylation	17 (18.1)	3 (13.0)	10 (20.8)	4 (19.0)		13 (18.3)		3 (13.6)	10 (20.4)	4 (17.4)		13 (18.3)
MGMT gene
Unmethylation	46 (48.9)	8 (34.8)	26 (54.2)	12 (57.1)	0.24	34 (47.9)	0.62	8 (36.4)	25 (51.0)	13 (56.5)	0.37	33 (46.5)	0.55
Methylation	48 (51.1)	15 (65.2)	22 (45.8)	9 (42.9)		37 (52.1)		14 (63.6)	24 (49.0)	10 (43.5)		38 (53.5)
Death in 5 yr
No	76 (80.9)	21 (91.3)	41 (85.4)	13 (61.9)	0.03	62 (87.3)	0.02	20 (90.9)	42 (85.7)	14 (60.9)	0.02	62 (87.3)	0.01
Yes	18 (19.1)	2 (8.7)	7 (14.6)	8 (38.1)		9 (12.7)		2 (9.1)	7 (14.3)	9 (39.1)		9 (12.7)

^aThe total number of patients with colorectal cancer does not correspond because of missing data. CRC: Colorectal cancer.

Table 3 Clinical characteristics of colorectal cancer patients and MTNR1B genotypes (rs10830963 and rs1447352)

Variables	Total	rs10830963 (C>G)						rs1447352 (A>G)
Variables	Total	CC (%)	CG (%)	GG (%)	P value	CC + CG (%)	P value	GG (%)	GA (%)	AA (%)	P value	GG + GA (%)	P value
Sex
Male	39 (41.5)	7 (33.3)	22 (44.9)	10 (43.5)	0.66	29 (41.4)	1.00	4 (66.7)	16 (43.2)	19 (38.0)	0.40	20 (46.5)	0.53
Female	55 (58.5)	14 (66.7)	27 (55.1)	13 (56.5)		41 (58.6)		2 (33.3)	21 (56.8)	31 (62.0)		23 (53.5)
Age at surgery
mean ± SD (yr)	64.2 ± 13.8	67.0 ± 14.0	61.4 ± 13.9	66.8 ± 13.1	0.16	63.1 ± 14.0	0.26	69.7 ± 14.1	64.4 ± 14.0	63.0 ± 13.8	0.53	65.1 ± 14.0	0.47
< 65	50 (53.2)	11 (52.4)	28 (57.1)	11 (47.8)	0.75	39 (55.7)	0.63	3 (50.0)	18 (48.6)	29 (58.0)	0.68	21 (48.8)	0.41
≥ 65	44 (46.8)	10 (47.6)	21 (42.9)	12 (52.2)		31 (44.3)		3 (50.0)	19 (51.4)	21 (42.0)		22 (51.2)
Stage
I	12 (12.8)	2 (9.5)	6 (12.2)	4 (17.4)	0.56	8 (11.4)	0.30	0 (0)	4 (10.8)	8 (16.0)	0.54	4 (9.3)	0.60
II	34 (36.2)	8 (38.1)	18 (36.7)	7 (30.4)		26 (37.1)		1 (16.7)	15 (40.5)	17 (34.0)		16 (37.2)
III	30 (31.9)	9 (42.9)	16 (32.7)	5 (21.7)		25 (35.7)		4 (66.7)	12 (32.4)	14 (28.0)		16 (37.2)
IV	18 (19.1)	2 (9.5)	9 (18.4)	7 (30.4)		11 (15.7)		1 (16.7)	6 (16.2)	11 (22.0)		7 (16.3)
Adjuvant chemotherapy^a
No	23 (24.5)	5 (23.8)	12 (25.5)	6 (30.0)	0.90	17 (25.0)	0.77	1 (16.7)	8 (22.2)	14 (30.4)	0.61	9 (21.4)	0.47
Yes	65 (69.1)	16 (76.2)	35 (74.5)	14 (70.0)		51 (75.0)		5 (83.3)	28 (77.8)	32 (69.6)		33 (78.6)
Tumor location^a
Colon	74 (78.7)	20 (95.2)	41 (87.2)	13 (65.0)	0.02	61 (89.7)	0.01	6 (100)	34 (94.4)	34 (73.9)	0.02	40 (95.2)	< 0.001
Rectum	14 (14.9)	1 (4.85)	6 (12.8)	7 (35.0)		7 (10.3)		0 (0)	2 (5.6)	12 (26.1)		2 (4.8)
CDKN2A gene
Unmethylation	43 (45.7)	12 (57.1)	17 (34.7)	13 (56.5)	0.10	29 (41.4)	0.31	4 (66.7)	16 (43.2)	22 (44.0)	0.55	20 (46.5)	0.97
Methylation	51 (54.3)	9 (42.9)	32 (65.3)	10 (43.5)		41 (58.6)		2 (33.3)	21 (56.8)	28 (56.0)		23 (53.5)
MLH1 gene
Unmethylation	77 (81.9)	18 (85.7)	39 (79.6)	19 (82.6)	0.83	57 (81.4)	1.00	5 (83.3)	31 (83.8)	40 (80.0)	0.90	36 (83.7)	0.79
Methylation	17 (18.1)	3 (14.3)	10 (20.4)	4 (17.4)		13 (18.6)		1 (16.7)	6 (16.2)	10 (20.0)		7 (16.3)
MGMT gene
Unmethylation	46 (48.9)	8 (38.1)	26 (53.1)	12 (52.2)	0.50	34 (48.6)	0.95	4 (66.7)	18 (48.6)	24 (48.0)	0.68	22 (51.2)	0.92
Methylation	48 (51.1)	13 (61.9)	23 (46.9)	11 (47.8)		36 (51.4)		2 (33.3)	19 (51.4)	26 (52.0)		21 (48.8)
Death in 5 yr
No	76 (80.9)	19 (90.5)	43 (87.8)	13 (56.5)	< 0.001	62 (88.6)	< 0.001	6 (100)	33 (89.2)	36 (72.0)	0.06	39 (90.7)	0.03
Yes	18 (19.1)	2 (9.5)	6 (12.2)	10 (43.5)		8 (11.4)		0 (0)	4 (10.8)	14 (28.0)		4 (9.3)

^aThe total number of patients with colorectal cancer does not correspond because of missing data. CRC: Colorectal cancer.

Table 4 Relationship between MTNR1B single-nucleotide polymorphism and 5-year overall survival of colorectal cancer patients

	No. of subjects	No. of cases (%)	Crude		Adjusted^a
	No. of subjects	No. of cases (%)	HR	95%CI	HR	95%CI
rs1387153 (C>T)
CC	23	2 (11.8)	1.00	Referent	1.00	Referent
CT	48	7 (41.2)	1.65	(0.34 to 7.95)	1.98	(0.40 to 9.82)
TT	21	8 (47.1)	6.03	(1.28 to 28.4)	10.6	(1.87 to 59.5)
TT vs CC + CT			4.18	(1.61 to 10.9)	6.23	(2.01 to 19.3)
rs2166706 (T>C)
TT	22	2 (11.1)	1.00	Referent	1.00	Referent
TC	49	7 (38.9)	1.55	(0.32 to 7.47)	1.91	(0.39 to 9.45)
CC	23	9 (50.0)	5.74	(1.24 to 26.6)	10.5	(1.96 to 56.4)
CC vs TT + TC			4.15	(1.65 to 10.5)	6.40	(2.21 to 18.6)
rs10830963 (C>G)
CC	21	2 (11.1)	1.00	Referent	1.00	Referent
CG	49	6 (33.3)	1.19	(0.24 to 5.91)	1.40	(0.27 to 7.22)
GG	23	10 (55.6)	5.79	(1.27 to 26.5)	9.46	(1.90 to 47.1)
GG vs CC + CG			5.09	(2.01 to 12.9)	7.43	(2.63 to 21.1)
rs1447352 (A>G)
AA	50	14 (77.8)	1.00	Referent	1.00	Referent
GA	37	4 (22.2)	0.36	(0.12 to 1.08)	0.31	(0.10 to 0.99)
GG	6	0 (0)	N/A	N/A	N/A	N/A
AA vs GG + GA			3.37	(1.11 to 10.2)	4.28	(1.32 to 13.9)

^aAdjusted for age, sex, stage, adjuvant chemotherapy, tumor location and the methylation status of CDKN2A, MLH1 and MGMT gene. HR: Hazard ratio; N/A: Not applicable.

Table 5 Stratified effect between gene promoter region methylation and MTNR1B genotypes for 5-year overall survival of colorectal cancer patients

		No. of subjects	No. of cases (%)	Crude		Adjusted^a
		No. of subjects	No. of cases (%)	HR	95%CI	HR	95%CI
rs1387153 (C>T)
TT vs CC + CT	CDKN2A
	U	10	4 (40.0)	5.01	(1.33 to 18.9)	10.4	(1.17 to 92.4)
	M	11	4 (36.4)	3.83	(0.96 to 15.3)	8.86	(1.08 to 72.8)
	MGMT
	U	12	5 (41.7)	3.63	(1.05 to 12.6)	8.57	(1.67 to 44.1)
	M	9	3 (33.3)	4.93	(1.10 to 22.1)	3.05	(0.33 to 28.0)
rs2166706 (T>C)
CC vs TT + TC	CDKN2A
	U	10	4 (40.0)	5.02	(1.33 to 19.0)	10.4	(1.17 to 92.4)
	M	13	5 (38.5)	3.96	(1.06 to 14.7)	10.1	(1.49 to 68.0)
	MGMT
	U	13	5 (38.5)	3.07	(0.89 to 10.7)	6.28	(1.54 to 25.7)
	M	23	9 (39.1)	6.25	(1.56 to 25.1)	8.28	(0.95 to 72.3)
rs10830963 (C>G)
GG vs CC + CG	CDKN2A
	U	13	5 (38.5)	4.63	(1.24 to 17.3)	8.47	(1.57 to 45.6)
	M	10	5 (50.0)	5.61	(1.51 to 20.9)	27.2	(3.12 to 233)
	MGMT
	U	12	5 (41.7)	3.47	(1.00 to 12.0)	8.50	(1.98 to 36.5)
	M	11	5 (45.5)	7.91	(1.89 to 33.2)	9.80	(1.42 to 67.5)
rs1447352 (A>G)
AA vs GG + GA	CDKN2A
	U	22	6 (27.3)	2.05	(0.51 to 8.22)	2.28	(0.51 to 10.2)
	M	28	8 (28.6)	7.34	(0.92 to 58.7)	9.40	(1.02 to 86.8)
	MGMT
	U	24	8 (33.3)	3.94	(0.84 to 18.6)	19.4	(2.94 to 128)
	M	26	6 (23.1)	2.77	(0.56 to 13.7)	2.04	(0.35 to 12.0)

^aAdjusted for age, sex, stage, adjuvant chemotherapy, tumor location and the methylation status of CDKN2A and MLH1 or MGMT and MLH1 gene. U: Unmethylation; M: Methylation; HR: Hazard ratio.

Table 6 Cumulative effect of MTNR1B single-nucleotide polymorphism associated with 5-year overall survival of colorectal cancer patients

	No. of subjects	No. of cases (%)	Crude		Adjusted^a
	No. of subjects	No. of cases (%)	HR	95%CI	HR	95%CI
No. of SNP risk genotypes
0	41	3 (7.3)	1.00	Referent	1.00	Referent
1	25	4 (16.0)	2.27	(0.51 to 10.1)	2.60	(0.55 to 12.2)
2	7	3 (42.9)	6.40	(1.29 to 317)	6.89	(1.16 to 41.0)
3	1	0 (0)	N/A	N/A	N/A	N/A
4	18	7 (38.9)	7.60	(1.96 to 29.5)	14.0	(2.94 to 66.3)
P for trend				< 0.001		< 0.001
≥ 2 of SNP risk genotypes	26	10 (38.5)	4.00	(1.58 to 10.1)	5.81	(2.03 to 16.6)

^aAdjusted for age, sex, stage, adjuvant chemotherapy, tumor location and the methylation status of CDKN2A, MLH1 and MGMT gene. SNP: Single-nucleotide polymorphism; U: Unmethylation; M: Methylation; HR: Hazard ratio; N/A: Not applicable.

Table 7 Relationship between haplotypes of MTNR1B single-nucleotide polymorphism and 5-year overall survival of colorectal cancer patients

Haplotypes	Survival group (%)	Death group (%)	Crude		Adjusted^a
Haplotypes	Survival group (%)	Death group (%)	HR	95%CI	HR	95%CI
T-C-G-A	42.0	68.4	2.58	(1.27 to 5.28)	2.75	(1.82 to 11.2)
C-T-G-A	2.7	5.3	1.74	(0.42 to 7.26)	1.96	(0.44 to 8.66)
C-T-C-G	30.0	7.9	0.23	(0.07 to 0.76)	0.21	(0.06 to 0.71)
C-T-C-A	22.0	15.8	0.73	(0.30 to 1.76)	0.70	(0.28 to 1.72)

^aAdjusted for age, sex, stage, adjuvant chemotherapy, tumor location. The reference is the set of all the other haplotypes when one haplotype is regarded as an analyzed item. HR: Hazard ratio.

Citation: Lee CC, Kuo YC, Hu JM, Chang PK, Sun CA, Yang T, Li CW, Chen CY, Lin FH, Hsu CH, Chou YC. MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan. World J Gastroenterol 2021; 27(34): 5737-5752
URL: https://www.wjgnet.com/1007-9327/full/v27/i34/5737.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i34.5737