Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan

doi:10.3748/wjg.v28.i8.825

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World Journal of Gastroenterology

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Retrospective Cohort Study

World J Gastroenterol. Feb 28, 2022; 28(8): 825-839
Published online Feb 28, 2022. doi: 10.3748/wjg.v28.i8.825

Table 1 Primer sequences, annealing temperature and product size for MS-PCR and EpiTYPER DNA methylation analysis of target genes

Genes		Forward primer (5’ → 3’)	Annealing temperature (°C)	Product size (bp)
SUMF2	M	F:TTTGATTATGGTCGGTTTTGC	59.4	191
	M	R:GACTACTTACAACTCCCCTAACGAC	59.4	191
	U	F:TTTTTTGATTATGGTTGGTTTTGTG	60.6	198
	U	R:CCCAACTACTTACAACTCCCCTAACA	60.6	198
	Q	F:TTTGTTATAGAGGGATGGGAGATAG aggaagagag	60	232
	Q	R:CAAAATAAACAACACTCCAAATTCA cagtaatacgactcactatagggagaaggct	60	232
ADAMTS5	M	F:GTTATTGTCGTGGAGCGTTAGC	59.4	170
	M	R:CCTACCTCCCGTACTTCCCG	59.4	170
	U	F:TTATTGTTGTGGAGTGTTAGTGTTT	59.4	169
	U	R:CCTACCTCCCATACTTCCCACAT	59.4	169
	Q	F:aggaagagagTTGAAATTGTTATTGTAGGATGGTATG	61.3	245
	Q	R:cagtaatacgactcactatagggagaaggctAATTAAAACAAAAATACAAAAAAACAACC	61.3	245
PXDN	M	F:TATGCGGGACGAGAACGAGA	61.6	137
	M	R:ACTTAAACAACTCCGTAACAATACGAT	61.6	137
	U	F:GTGTATGTGGGATGAGAATGAGAG	60.4	142
	U	R:CAACTTAAACAACTCCATAACAATACAA	60.4	142

MS-PCR: Methylation-specific polymerase chain reaction; SUMF2: Sulfatase modifying factor 2; ADAMTS5: ADAM metallopeptidase with thrombospondin type 1 motif 5; PXDN: Peroxidasin; M: Methylation; U: Unmethylation; Q: Quantitative analysis.

Table 2 Characteristics and distribution of methylation status in patients with colorectal cancer (n = 208)

Characteristics	Total	Methylation status
		*SUMF2*		*ADAMTS5*		*PXDN*
		Normal	Tumor	Normal	Tumor	Normal	Tumor
Sex
Male	103 (49.5)	20 (60.6)	27 (55.1)	28 (60.9)	44 (77.2)	35 (76.1)	44 (77.2)
Female	105 (50.5)	17 (45.9)	25 (45.5)	38 (64.4)	49 (73.1)	41 (69.5)	53 (79.1)
χ² (P value)		0.97 (0.324)	0.62 (0.432)	0.03 (0.866)	0.1 (0.755)	0.28 (0.596)	< 0.01 (0.969)
Age at surgery
mean ± SD	64.3 ± 14.6	64.9 ± 14.2	66.9 ± 15.8	66.4 ± 14.8	67.7 ± 15.5	65.0 ± 14.4	66.2 ± 15.0
< 65	103 (49.5)	17 (51.5)	26 (53.1)	28 (58.3)	43 (72.9)	34 (70.8)	46 (78.0)
≥ 65	105 (50.5)	20 (54.1)	26 (47.3)	38 (66.7)	50 (76.9)	42 (73.7)	51 (78.5)
χ² (P value)		< 0.01 (1.00)	0.15 (0.694)	0.46 (0.498)	0.1 (0.755)	0.01 (0.915)	< 0.01(1.00)
Stage
I	29 (13.9)	7 (58.3)	7 (50.0)	9 (50.0)	12 (63.2)	12 (66.7)	17 (89.5)
II	77 (37.0)	13 (48.1)	17 (45.9)	21 (56.8)	33 (75.0)	29 (78.4)	39 (88.6)
III	68 (32.7)	13 (65.0)	21 (63.6)	22 (68.8)	31 (75.6)	22 (68.8)	27 (65.9)
IV	34 (16.3)	4 (36.4)	7 (35.0)	14 (77.8)	17 (85.0)	13 (72.2)	14 (70.0)
χ² (P value)		2.77 (0.429)	4.5 (0.212)	4.06 (0.255)	2.5 (0.476)	1.17 (0.760)	8.69^a (0.034)
5-yr recurrence¹
No	141 (82.0)	28 (51.9)	35 (49.3)	43 (56.6)	61 (70.9)	54 (71.1)	71 (82.6)
Yes	31 (18.0)	4 (40.0)	9 (60.0)	12 (80.0)	14 (82.4)	11 (73.3)	12 (70.6)
χ² (P value)		0.12 (0.731)	0.22 (0.639)	1.98 (0.160)	0.45 (0.504)	< 0.01 (1.00)	0.65 (0.421)
5-yr all-cause death
No	168 (80.8)	29 (54.7)	43 (51.8)	50 (61.0)	79 (78.2)	59 (72.0)	77 (76.2)
Yes	40 (19.2)	8 (47.1)	9 (42.9)	16 (69.6)	14 (60.9)	17 (73.9)	20 (87.0)
χ² (P value)		0.07 (0.786)	0.24 (0.625)	0.26 (0.611)	2.15 (0.142)	< 0.01 (1.00)	0.71 (0.399)
5-yr progression
No	155 (74.5)	28 (56.0)	39 (50.0)	45 (58.4)	73 (76.8)	56 (72.7)	74 (77.9)
Yes	53 (25.5)	9 (45.0)	13 (50.0)	21 (75.0)	20 (69.0)	20 (71.4)	23 (79.3)
χ² (P value)		0.32 (0.570)	< 0.01(1.00)	1.75 (0.185)	0.38 (0.540)	< 0.01 (1.00)	< 0.01 (1.00)
Lymphovascular invasion¹
No	106 (52.5)	20 (48.8)	25 (48.1)	32 (56.1)	46 (73.0)	41 (71.9)	55 (87.3)
Yes	96 (47.5)	16 (57.1)	27 (51.9)	34 (72.3)	47 (78.3)	34 (72.3)	41 (68.3)
χ² (P value)		0.19 (0.662)	0.04 (0.845)	2.26 (0.133)	0.23 (0.634)	< 0.01 (1.00)	5.44^a (0.02)
Histological grade¹
Well or moderately	156 (89.7)	27 (48.2)	35 (47.3)	52 (64.2)	67 (74.4)	58 (71.6)	67 (74.4)
Poor or undifferentiated	18 (10.3)	6 (100.0)	9 (64.3)	7 (70.0)	14 (82.4)	9 (90.0)	13 (76.5)
χ² (P value)		3.94^a(0.047)	0.76 (0.382)	< 0.01 (0.99)	0.15 (0.697)	0.75 (0.387)	< 0.01 (1.00)
Lymph node counts¹
0-11	34 (18.4)	7 (63.6)	7 (50.0)	12 (80.0)	15 (83.3)	13 (86.7)	16 (88.9)
≥ 12	151 (81.6)	29 (52.7)	40 (50.0)	50 (61.7)	70 (73.7)	58 (71.6)	70 (73.7)
χ² (P value)		0.07 (0.786)	< 0.01 (1.00)	1.14 (0.287)	0.33 (0.568)	0.81 (0.368)	1.18 (0.278)
Tumor location¹
Colon	147 (79.9)	28 (50.0)	38 (50.7)	53 (67.9)	62 (70.5)	60 (76.9)	68 (77.3)
Rectum	37 (20.1)	8 (80.0)	9 (47.4)	9 (50.0)	23 (92.0)	11 (61.1)	18 (72.0)
χ² (P value)		1.99 (0.158)	< 0.01(1.00)	1.35 (0.245)	3.76 (0.052)	1.17 (0.280)	0.08 (0.780)
Adjuvant chemotherapy¹
No	54 (29.3)	10 (58.8)	12 (42.9)	15 (55.6)	25 (73.5)	20 (74.1)	29 (85.3)
Yes	130 (70.7)	26 (53.1)	35 (53.0)	47 (68.1)	60 (75.9)	51 (73.9)	57 (72.2)
χ² (P value)		0.02 (0.898)	0.46 (0.499)	0.85 (0.358)	0.01 (0.971)	< 0.01(1.00)	1.59 (0.207)

¹The total number of colorectal cancer patients does not correspond because of missing data.

^aP < 0.05. SUMF2: Sulfatase modifying factor 2; ADAMTS5: ADAM metallopeptidase with thrombospondin type 1 motif 5; PXDN: Peroxidasin; SD: Standard deviation.

Table 3 Methylation level of sulfatase modifying factor 2 and ADAM metallopeptidase with thrombospondin type 1 motif 5 in normal tissue and tumor tissue (n= 208)

	Normal			Tumor			P value
	n¹	Median	mean ± SD²	n¹	Median	mean ± SD²	P value
SUMF2
CpG_1	69	0.40	0.43 ± 0.15	104	0.53	0.55 ± 0.17	< 0.001
CpG_2	70	0.56	0.56 ± 0.11	104	0.76	0.73 ± 0.13	< 0.001
CpG_3	70	0.38	0.39 ± 0.11	104	0.54	0.54 ± 0.17	< 0.001
CpG_7	48	0.64	0.64 ± 0.15	80	0.87	0.81 ± 0.20	0.001
ADAMTS5
CpG_1	66	0.06	0.08 ± 0.07	95	0.19	0.25 ± 0.20	< 0.001
CpG_2	70	0.06	0.08 ± 0.06	105	0.20	0.24 ± 0.18	< 0.001
CpG_9	69	0.06	0.07 ± 0.06	91	0.21	0.25 ± 0.18	< 0.001
CpG_10.11	69	0.08	0.10 ± 0.09	103	0.30	0.34 ± 0.22	< 0.001
CpG_12	65	0.09	0.10 ± 0.08	98	0.19	0.24 ± 0.21	0.001
CpG_13	63	0.07	0.12 ± 0.14	94	0.15	0.22 ± 0.22	0.009
CpG_14.15	71	0.32	0.33 ± 0.05	105	0.43	0.44 ± 0.11	< 0.001
CpG_16	71	0.10	0.11 ± 0.04	105	0.19	0.22 ± 0.12	< 0.001

¹The total number of colorectal cancer patients does not correspond because of missing data.

²Represent the ratio of DNA methylation.

SD: Standard deviation; SUMF2: Sulfatase modifying factor 2; ADAMTS5: ADAM metallopeptidase with thrombospondin type 1 motif 5.

Table 4 Multivariate 5-year progression and survival analysis of SUMF2 and ADAMTS5 gene

	RFS		PFS		OS
	cHR (95%CI)	aHR (95%CI)¹	cHR (95%CI)	aHR (95%CI)¹	cHR (95%CI)	aHR (95%CI)²
SUMF2 in tumor tissue
CpG_3+CpG_7
Hypomethylation	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
Hypermethylation	2.37 (0.86-6.55)	1.64 (0.55-4.89)	2.24 (1.03-4.85)^a	2.05 (0.91-4.62)	2.56 (1.08-6.04)^a	3.53 (1.35-9.26)^a
ADAMTS5 in normal tissue
CpG_2
Hypomethylation	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
Hypermethylation	0.15 (0.03-0.71)^a	0.17 (0.03-0.95)^a	0.57 (0.24-1.37)	0.54 (0.21-1.41)	0.82 (0.31-2.16)	0.94 (0.31-2.85)
CpG_13
Hypomethylation	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)	1.00 (Reference)
Hypermethylation	0.20 (0.04-0.97)^a	0.16 (0.03-0.85)^a	0.48 (0.19-1.19)	0.45 (0.17-1.18)	0.50 (0.19-1.30)	0.72 (0.24-2.15)

¹Adjusted for sex, age, and stage.

²Adjusted for sex, age, stage, and lymph node counts.

^aP < 0.05. RFS: Recurrence-free survival; PFS: Progression-free survival; OS: Overall survival; cHR: Crude hazard ratio; aHR: Adjusted hazard ratio; CI: Confidence interval; SUMF2: Sulfatase modifying factor 2; ADAMTS5: ADAM metallopeptidase with thrombospondin type 1 motif 5.

Citation: Su JQ, Lai PY, Hu PH, Hu JM, Chang PK, Chen CY, Wu JJ, Lin YJ, Sun CA, Yang T, Hsu CH, Lin HC, Chou YC. Differential DNA methylation analysis of SUMF2, ADAMTS5, and PXDN provides novel insights into colorectal cancer prognosis prediction in Taiwan. World J Gastroenterol 2022; 28(8): 825-839
URL: https://www.wjgnet.com/1007-9327/full/v28/i8/825.htm
DOI: https://dx.doi.org/10.3748/wjg.v28.i8.825