Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan

doi:10.3748/wjg.v26.i2.154

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Retrospective Cohort Study

World J Gastroenterol. Jan 14, 2020; 26(2): 154-167
Published online Jan 14, 2020. doi: 10.3748/wjg.v26.i2.154

Table 1 Characteristics and distribution of methylation status in patients with colorectal cancer (n = 120), n (%)

Variables	Total	Methylation status
		*OAF*		≥ 3 of genes¹
		Normal	Tumors	Normal	Tumors
Sex
Male	60 (50.0)	13 (28.9)	28 (62.2)	16 (26.7)	41 (68.3)
Female	60 (50.0)	16 (34.8)	34 (73.9)	19 (31.7)	41 (68.3)
Age in yr at surgery
Mean (SD)	63.8 (14.8)	62.6 (12.6)	63.2 (15.0)	62.5 (13.5)	62.5 (15.3)
< 65	61 (50.8)	15 (30.0)	33 (66.0)	19 (31.1)	45 (73.8)
≥ 65	59 (49.2)	14 (34.1)	29 (70.7)	16 (27.1)	37 (62.7)
Stage
	19 (15.8)	2 (16.7)	6 (50.0)	6 (31.6)	10 (52.6)
	39 (32.5)	6 (20.7)	22 (75.9)	11 (28.2)	26 (66.7)
	40 (33.3)	14 (45.2)	22 (71.0)	11 (27.5)	29 (72.5)
	22 (18.3)	7 (36.8)	12 (63.2)	7 (31.8)	17 (77.3)
Adjuvant chemotherapy
No	32 (28.3)	5 (22.7)	13 (59.1)	13 (40.6)	23 (71.9)
Yes	81 (71.7)	24 (36.9)	46 (70.8)	22 (27.2)	55 (67.9)
Lymph/vascular invasion
No	44 (97.8)	12 (35.3)	21 (61.8)	18 (40.9)	28 (63.6)
Yes	1 (2.2)	0 (0)	1 (100.0)	0 (0)	1 (100.0)
Histological grade²
Well or Moderately	96 (88.9)	23 (31.9)	45 (62.5)	31 (32.3)	62 (64.6)
Poor or undifferentiated	12 (11.1)	5 (45.5)	10 (90.9)	2 (16.7)	11 (91.7)
Tumor location²
Colon	89 (78.8)	19 (28.4)	46 (68.7)	27 (30.3)	59 (66.3)
Rectum	24 (21.2)	10 (50.0)	13 (65.0)	8 (33.3)	19 (79.2)
Progression in 5 yr
No	75 (62.5)	11 (22.0)^a	33 (66.0)	17 (22.7)^a	46 (61.3)
Yes	45 (37.5)	18 (43.9)	29 (70.7)	18 (40.0)	36 (80.0)
All-cause death in 5 yr
No	97 (80.8)	22 (31.0)	50 (70.4)	28 (28.9)	67 (69.1)
Yes	23 (19.2)	7 (35.0)	12 (60.0)	7 (30.4)	15 (65.2)

¹Including CDKN2A, hMLH1, MGMT, CSF2, DIS3L2, and OAF.

²The total number of patients with colorectal cancer does not correspond because of missing data.

^aP < 0.05. OAF: The out at first homolog gene; SD: Standard deviation.

Table 2 Relationship between the number of hypermethylated genes and 5-year time to progression of colorectal cancer patients, n (%)

	Normal tissues						Tumor tissues
	No. of subjects	No. of cases	Crude		Adjusted		No. of subjects	No. of cases	Crude		Adjusted
	No. of subjects	No. of cases	HR	95%CI	HR	95%CI	No. of subjects	No. of cases	HR	95%CI	HR	95%CI
NO. of hypermethylated genes
0	9	3 (33.3)	1.00	Referent	1.00	Referent	3	1 (33.3)	1.00	Referent	1.00	Referent
1	34	8 (23.5)	0.76	0.15-3.74	0.64	0.13-3.23	7	0 (0)	N/A	N/A	N/A	N/A
2	42	16 (38.1)	1.58	0.36-6.94	1.62	0.34-7.62	28	8 (28.6)	0.47	0.05-4.20	0.65	0.07-5.88
3	21	12 (57.1)	2.66	0.58-12.19	2.18	0.46-10.4	39	15 (38.5)	1.02	0.13-7.86	1.36	0.17-10.7
4	11	3 (27.3)	1.28	0.21-7.65	1.48	0.18-12.2	23	14 (60.9)	2.12	0.28-16.3	2.56	0.33-20.2
5	3	3 (100)	7.26^a	1.00-52.84	4.70	0.57-39.0	17	6 (35.3)	1.17	0.14-9.71	1.52	0.17-13.5
6	0	0	N/A	N/A	N/A	N/A	3	1 (33.3)	1.13	0.07-18.0	2.10	0.12-38.3
P value¹				0.02		0.02				0.02		0.02
≥ 3 of genes²	35	18 (51.4)	1.99^a	1.03-3.85	2.01^a	1.00-4.01	82	36(43.9)	3.26^a	1.27-8.39	3.18^a	1.21-8.39

¹P for trend.

²Including CDKN2A, hMLH1, MGMT, CSF2, DIS3L2, and OAF.

^aP < 0.05. Adjusted for gender, age at surgery (continuous), adjuvant chemotherapy, histological grade, and tumor location. CI: Confidence interval; HR: Hazard ratio; N/A: Not applicable.

Table 3 Relationship between the number of hypermethylated genes and 5-year overall survival of colorectal cancer patients, n (%)

	Normal tissues						Tumor tissues
	No. of subjects	No. of cases	Crude		Adjusted		No. of subjects	No. of cases	Crude		Adjusted
	No. of subjects	No. of cases	HR	95%CI	HR	95%CI	No. of subjects	No. of cases	HR	95%CI	HR	95%CI
NO. of methylated genes
0	9	1 (11.11)	1.00	Referent	1.00	Referent	3	1 (33.33)	1.00	Referent	1.00	Referent
1	34	7 (20.59)	1.52	0.19-12.4	1.19	0.14-10.1	7	0 (0)	N/A	N/A	N/A	N/A
2	42	8 (19.05)	1.76	0.22-14.1	0.89	0.10-8.40	28	7 (25)	0.95	0.12-7.72	0.73	0.08-6.55
3	21	4 (19.05)	1.79	0.20-16.0	1.41	0.15-13.2	39	6 (15.38)	0.66	0.08-5.47	0.59	0.07-5.2
4	11	2 (18.18)	2.11	0.19-23.3	1.40	0.10-18.8	23	6 (26.09)	1.24	0.15-10.3	1.16	0.13-10.2
5	3	1 (33.33)	4.89	0.30-78.8	4.91	0.29-83.4	17	3 (17.65)	0.84	0.09-8.06	0.60	0.05-7.13
6	0	0 (0)	N/A	N/A	N/A	N/A	3	0 (0)	N/A	N/A	N/A	N/A
P value¹				0.33		0.40				0.59		0.64
≥ 3 of genes²	35	7 (20.0)	1.31	0.54-3.18	1.50	0.59-3.81	82	15 (18.3)	1.13	0.48-2.66	1.21	0.47-3.10

Adjusted for gender, age at surgery (continuous), adjuvant chemotherapy, histological grade and tumor location.

¹P for trend.

²Including CDKN2A, hMLH1, MGMT, CSF2, DIS3L2, and OAF. CI: Confidence interval; HR: Hazard ratio; N/A: Not applicable.

Table 4 Interaction between gene promoter region methylation and different cancer stages for 5-year time to progression of colorectal cancer patients, n (%)

	Normal tissues						Tumor tissues
	No. of subjects	No. of cases	Crude		Adjusted		No. of subjects	No. of cases	Crude		Adjusted
	No. of subjects	No. of cases	HR	95%CI	HR	95%CI	No. of subjects	No. of cases	HR	95%CI	HR	95%CI
OAF
UnMe/local (1 and 2)¹	33	3 (9.1)	1.00	Referent	1.00	Referent	13	0 (0.0)	1.00	Referent	1.00	Referent
UnMe/advanced (3 and 4)²	29	20 (69.0)	14.7^a	3.38-63.6	16.6^a	3.69-74.6	16	12 (75.0)	N/A	N/A	N/A	N/A
Me/local (1 and 2)³	8	0 (0.0)	N/A	N/A	N/A	N/A	28	3 (10.7)	N/A	N/A	N/A	N/A
Me/advanced (3 and 4)⁴	21	18 (85.7)	19.0^a	4.30-84.6	20.3^a	4.12-100	34	26 (76.5)	N/A	N/A	N/A	N/A
P value¹				< 0.01		< 0.01
≥ 3 of genes⁶
UnMe/local (1 and 2)¹	41	2 (4.88)	1.00	Referent	1.00	Referent	22	2 (9.09)	1.00	Referent	1.00	Referent
UnMe/advanced (3 and 4)²	44	25 (56.8)	13.3^a	3.10-57.0	11.9^a	2.72-51.8	16	7 (43.8)	7.17	0.80-64.2	6.56	0.72-59.4
Me/local (1 and 2)³	17	1 (5.88)	N/A	N/A	N/A	N/A	36	1 (2.78)	0.63	0.04-9.99	0.59	0.04-9.62
Me/advanced (3 and 4)⁴	18	17 (94.4)	33.4^a	7.49-149	28.8^a	6.24-133	46	35 (76.1)	23.1^a	3.14-170	20.8^a	2.75-157
P value⁵				< 0.01		< 0.01				< 0.01		< 0.01

¹DNA promoter region unmethylation with cancer stage 1 or 2;

²DNA promoter region unmethylation with cancer stage 3 or 4;

³DNA promoter region methylation with cancer stage 1 or 2;

⁴Me/advanced (3 and 4): DNA promoter region methylation with cancer stage 3 or 4;

⁵P for the joint effect interaction;

⁶Including CDKN2A, hMLH1, MGMT, CSF2, DIS3L2, and OAF.

^aP < 0.05. Adjusted for gender, age at surgery (continuous), adjuvant chemotherapy, histological grade, and tumor location. CI: Confidence interval; HR: Hazard ratio; OAF: The out at first homolog gene; N/A: Not applicable.

Table 5 Interaction between gene promoter region methylation and different cancer stages for 5-year overall survival of colorectal cancer patients, n (%)

	Normal tissues						Tumor tissues
	No. of subjects	No. of cases	Crude		Adjusted		No. of subjects	No. of cases	Crude		Adjusted
	No. of subjects	No. of cases	HR	95%CI	HR	95%CI	No. of subjects	No. of cases	HR	95%CI	HR	95%CI
OAF
UnMe/local (1 and 2)¹	33	5 (15.2)	1.00	Referent	1.00	Referent	13	2 (15.4)	1.00	Referent	1.00	Referent
UnMe/advanced (3 and 4)²	29	8 (27.6)	2.24	0.73-6.86	4.84^a	1.22-19.2	16	6 (37.5)	3.12	0.63-15.5	15.7^a	1.98-124
Me/local (1 and 2)³	8	2 (25.0)	2.32	0.45-12.0	7.04	0.82-60.4	28	5 (17.9)	1.44	0.28-7.44	3.74	0.54-26.0
Me/advanced (3 and 4)⁴	21	5 (23.8)	1.85	0.53-6.41	5.96^a	1.16-30.6	34	7 (20.6)	1.78	0.37-8.60	6.86	0.93-50.5
P value⁵				0.33		0.03				0.47		0.06
≥ 3 of genes⁶
UnMe/local (1 and 2)¹	41	5 (12.2)	1.00	Referent	1.00	Referent	22	3 (13.6)	1.00	Referent	1.00	Referent
UnMe/advanced (3 and 4)²	44	11 (25.0)	2.57	0.89-7.40	5.28^a	1.35-20.6	16	5 (31.3)	2.68	0.64-11.2	5.53	1.00-30.6
Me/local (1 and 2)³	17	4 (23.5)	2.69	0.72-10.0	4.46	0.93-21.5	36	6 (16.7)	1.59	0.40-6.35	2.04	0.38-11.1
Me/advanced (3 and 4)⁴	18	3 (16.7)	1.86	0.44-7.82	4.27	0.76-23.8	46	9 (19.6)	2.09	0.56-7.76	3.93	0.78-19.8
P value⁵				0.40		0.10				0.27		0.10

¹DNA promoter region unmethylation with cancer stage 1 or 2;

²DNA promoter region unmethylation with cancer stage 3 or 4;

³DNA promoter region methylation with cancer stage 1 or 2;

⁴Me/advanced (3 and 4): DNA promoter region methylation with cancer stage 3 or 4;

⁵P for the joint effect interaction;

⁶Including CDKN2A, hMLH1, MGMT, CSF2, DIS3L2, and OAF.

Citation: Hsu CH, Hsiao CW, Sun CA, Wu WC, Yang T, Hu JM, Huang CH, Liao YC, Chen CY, Lin FH, Chou YC. Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan. World J Gastroenterol 2020; 26(2): 154-167
URL: https://www.wjgnet.com/1007-9327/full/v26/i2/154.htm
DOI: https://dx.doi.org/10.3748/wjg.v26.i2.154