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Table 2 Overall and stage-wise association of fecal DNA methylation markers with risk of colorectal neoplasms

From: Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review

Gene First author, year, Ref. No. Country Study group N DNAm assay OR (95% CI) p-valuea CRC stage N Stage-specific OR (95% CI) p-valuea p-value for methylation-stage associationb
CDKN2A (promoter) Abbaszadegan, 2007 [42] Iran CRC
Cn
25
20
MSP 11.0 (0.6–212.1)c 0.058
0.043d
II/B
III/C
14
5
4.6 (0.2–120.3)c
57.4 (2.3–1467.3)c
0.332
0.001
0.037e
COL4A1 (promoter/exon 1) Liu, 2019 [40] China AA
CRC
Cn
77
80
83
qMSP 10.3 (4.6–22.9)
57.6 (22.1–150.1)
< 0.001
< 0.001
I/II
III/IV
43
37
55.5 (17.7–174.0)
60.2 (17.6–206.1)
< 0.001
< 0.001
1.000
COL4A2 (promoter/exon 1) Liu, 2019 [40] China AA
CRC
Cn
77
80
83
qMSP 10.6 (4.3–25.9)
133.9 (43.0–417.2)
< 0.001
< 0.001
I/II
III/IV
43
37
105.9 (29.2–383.7)
190.0 (37.5–961.7)
< 0.001
< 0.001
0.815
FBN1 (promoter) Guo, 2013 [25] China CRC
Cn
75
30
MSP 36.0 (7.9–164.7) < 0.001 I
II
III
IV
12
30
30
3
154.0 (12.7–1875.6)
24.2 (4.8–121.6)
38.5 (7.4–199.9)
28.0 (1.7–458.8)
< 0.001
< 0.001
< 0.001
0.003
0.322
FBN1 (promoter) Li, 2015 [27] China CRC
Cn
89
30
MSP 33.9 (7.5–152.9)h < 0.001 I/A
II/B
III/C
17
36
36
45.5 (7.4–280.9)h
31.8 (6.4–157.6)h
86.8 (15.6–483.6)h
< 0.001
< 0.001
< 0.001
0.237
GATA4 (promoter) Hellebrekers, 2009 [37] Nether-lands CRC
Cn
47
30
qMSP 14.6 (3.1–68.4) < 0.001 I/II
III/IV
29
17
13.1 (2.6–65.3)
20.0 (3.5–112.7)
0.000
< 0.001
0.55e
GATA4 (promoter) Lu, 2014 [49] China CRC
Cn
56
40
MSP 14.3 (3.1–65) < 0.001 I/II
III/IV
32
24
11.4 (2.3–56.0)
19.0 (3.7–97.1)
0.0006
< 0.001
0.35
GATA5 (promoter) Lu, 2014 [49] China CRC
Cn
56
40
MSP 24.6 (8.3–72.7) < 0.001 I/II
III/IV
32
24
16.8 (5.2–54.2)
51.9 (9.9–273.2)
< 0.001
< 0.001
0.32
0.274e
HIC1 (promoter) Lenhard, 2005 Germany AA
CRC
Cn
13
26
50
MSP 21.8 (2.2–218.0)
35.9 (4.3–301.6)
0.001
< 0.001
I/II
III/IV
6
20
98.0 (7.2–1330.0)
16.3 (1.8–151.0)
< 0.001
0.0021
0.138e
ING1 (promoter) He, 2014 [26] China AA
CRC
Cn
27
61
20
n-MSP 32.3 (3.7–279.3)
53.4 (6.6–432.2)
< 0.001
< 0.001
A/B
C/D
33
28
43.7 (5.1–372.8)
69.7 (7.7–631.4)
< 0.001
< 0.001
0.432
ITGA4 (promoter/exon 1) Liu, 2019 [40] China AA
CRC
Cn
77
80
83
qMSP 19.0 (5.5–65.4)
125.7 (34.7–456.2)
< 0.001
< 0.001
I/II
III/IV
43
37
116.7 (29.2–466.1)
137.8 (32.4–585.4)
< 0.001
< 0.001
0.779
miR-34a (promoter) Wu, 2014 [36] China CRC
Cn
82
40
MSP 63.0 (13.9–285.7) < 0.001 I 13 30.4 (5.0–185.5) < 0.001 0.694
miR-34b/c (promoter) Wu, 2014 [36] China CRC
Cn
82
40
MSP 1097.2 (59.2–20349.1)c < 0.001 I 13 372.6 (16.7–8322.8)c < 0.001 0.656
miR-34b/c (promoter) Kalimutho, 2011 [33] Italy 0/ AA
CRC
Cn
5
23
39
MSP 10.2 (1.4–77.0)
24.5 (6.3–95.9)
0.011
< 0.001
I
II
III
2
6
3
31.4 (1.3–744.4)c
6.8 (1.1–43.5)
13.6 (1.0–179.0)
0.0032
0.0283
0.0172
0.727e
NDRG4 (promoter) Xiao , 2015 [32] China CRC
Cn
84
16
n-MSP -- -- I/II
III/IV
48
36
--
--
--
--
0.209f
NDRG4 (promoter) Lu, 2014 [49] China CRC
Cn
56
40
MSP 15.6 (2.0–123.4) 0.001 I/II
III/IV
32
24
10.9 (1.3–94.2)
23.4 (2.7–200.9)
0.0098
0.0002
0.200
OSMR (promoter) Kim, 2009 [24] Belgium CRC
Cn
69
81
qMSP 11.6 (3.8–35.6) < 0.001 I
II
III
IV
18
27
18
6
2.4 (0.4–14.3)
24.1 (6.8–84.8)
15.4 (3.9–60.6)
3.9 (0.4–41.2)
0.323
< 0.001
< 0.001
0.236
0.010e
RASSF2: Region 1 (promoter) Nagasaka, 2009 [45] Japan NAA
AA
Ad
CRC
Cn
29
27
56
84
113
Hi-SA
(n-MSP)
0.5 (0.0–10.7)c
8.3 (1.9–37.5)
3.6 (0.8–15.6)
13.8 (4.0–47.9)
0.678
0.001
0.072
< 0.001
I/II
III/IV
40
44
12.2 (3.2–47.2)
15.4 (4.1–57.4)
< 0.001
< 0.001
0.641f
RASSF2: Region 2 (promoter) Nagasaka, 2009 [45] Japan NAA
AA
Ad
CRC
Cn
29
27
56
84
113
Hi-SA
(n-MSP)
1.3 (0.1–13.1)
2.9 (0.5–18.5)
2.1 (0.4–10.6)
20.4 (6.0–69.7)
0.818
0.234
0.373
< 0.001
I/II
III/IV
40
44
10.7 (2.7–41.7)
33.5 (9.2–121.7)
< 0.001
< 0.001
0.015f
SDC2 Niu, 2017 [51] China AA
CRC
Cn
122
196
179
qMSP 19.4 (9.7–38.5)
59.8 (30.1–118.8)
< 0.001
< 0.001
I/II
III/IV
87
109
72.6 (32.0–164.5)
52.0 (24.7–109.6)
< 0.001
< 0.001
0.92
0.373f
SDC2 Han, 2019 [28] South Korea NAA
0/ AA
Ad
CRC
Cn
41
6
47
242
245
LTE-qMSP 3.0 (1.3–6.8)
46.0 (5.2–410.6)
4.3 (2.1–9.1)
83.6 (46.1–151.8)
0.008
< 0.001
< 0.001
< 0.001
I
II
III
IV
55
70
96
21
54.1 (22.9–127.8)
98.2 (38.5–250.7)
79.2 (36.4–172.5)
388.8 (22.8–6619.3)c
< 0.001
< 0.001
< 0.001
< 0.001
0.302e
SDC2 Oh, 2017 [35] South Korea NAA
CRC
Cn
21
50
22
LTE-qMSP 5.0 (0.9–27.7)
90.0 (16.1–503.8)
0.054
< 0.001
I
II
III
IV
12
17
10
11
50.0 (6.1–409.1)
75.0 (9.5–595.1)
90.0 (7.2–1125.5)
188.6 (8.3–4275.8)c
< 0.001
< 0.001
< 0.001
< 0.001
0.710e
SFRP2 (promoter) Kriegshäuser, 2017 [38] Austria CRC
Cn
2
22
MSRH
Methylt
10.0 (2.1–46.6) 0.002 I
II
16
18
27.9 (1.1–713.2)c
8.1 (1.7–39.1)
0.01
0.006
0.497e
SFRP2 (promoter) Zhang, 2014 [50] China NAA
AA
Ad
CRC
Cn
20
15
35
48
30
MSP 41.5 (2.2–774.6)c
89.2 (4.6–1733.0)c
64.5 (3.7–1137.2)c
78.0 (4.5–1350.0)c
0.000
< 0.001
< 0.001
< 0.001
I/A
II/B
III/C
IV/D
7
20
14
7
134.2 (5.6–3192.6)c
61.0 (3.3–1133.8)c
79.8 (4.1–1563.0)c
78.4 (3.5- 1783.6)c
< 0.001
< 0.001
< 0.001
< 0.001
0.812e
SFRP2 (promoter) Lu, 2014 [49] China CRC
Cn
56
40
MSP 12.0 (3.8–38.3) < 0.001 I/II
III/IV
32
24
9.0 (2.6–31.2)
18.0 (4.7–68.5)
0.0002
< 0.001
0.212
SFRP2 (promoter) Tang, 2011 [47] China AA
CRC
Cn
63
169
30
MSP 11.9 (2.6–54.5)
73.6 (16.6–327.5)
0.000
< 0.001
I/II
III/IV
99
70
67.5 (14.7–310.8)
84.0 (17.3–409.1)
< 0.001
< 0.001
0.614f
SFRP2: Region 1 (promoter) Nagasaka, 2009 [45] Japan NAA
AA
Ad
CRC
Cn
29
27
56
84
113
Hi-SA
(n-MSP)
4.4 (1.0–18.6)
11.5 (3.1–41.9)
7.4 (2.3–24.3)
36.3 (12.3–107.8)
0.033
< 0.001
0.000
< 0.001
I/II
III/IV
40
44
36.9 (11.4–119.8)
35.9 (11.2–114.7)
< 0.001
< 0.001
0.950f
SFRP2: Region 2 (promoter) Nagasaka, 2009 [45] Japan NAA
AA
Ad
CRC
Cn
29
27
56
84
113
Hi-SA
(n-MSP)
3.5 (0.9–13.8)
6.2 (1.7–22.1)
4.7 (1.5–14.5)
13.3 (4.9–36.1)
0.066
0.002
0.004
< 0.001
I/II
III/IV
40
44
13.0 (4.3–39.0)
13.6 (4.6–40.2)
< 0.001
< 0.001
0.915f
SFRP2 (promoter) Wang, 2008 [43] China AA
CRC
Cn
34
69
30
qMSP
(Methy-Light)
22.6 (4.6–111.2)
93.3 (18.9–460.7)
< 0.001
< 0.001
I/II
III/IV
30
39
70.0 (12.5–393.4)
122.5 (20.9–718.2)
< 0.001
< 0.001
0.433
0.488e
SNCA (promoter) Yang, 2017 [52] China Ad
CRC
Cn
49
31
64
qMSP 9.2 (3.8–22.6)g
11.3 (3.7–34.8)g
< 0.001
< 0.001
I/II
III/IV
17
13
14.0 (3.6–55.1)
16.5 (3.3–82.5)
< 0.001
< 0.001
1.000e
SNCA (promoter) Li, 2015 [27] China CRC
Cn
89
30
MSP 138.6 (8.2–2349.8)c, h < 0.001 I/A
II/B
III/C
17
36
36
107.9 (5.6–2073.1)c, h
239.9 (13.1–4391.9)c, h
119.6 (6.7–2122.1)c, h
< 0.001
< 0.001
< 0.001
0.323
SPART (promoter) Zhang, 2013 [48] China CRC
Cn
96
30
MSP 242.4 (14.2–4142.3)c < 0.001 I 21 117.9 (6.3–2209.1)c < 0.001 0.307
TLX2 (promoter/exon 1) Liu, 2019 [40] China AA
CRC
Cn
77
80
83
qMSP 32.0 (9.3–110.2)
210.4 (54.8–807.6)
< 0.001
< 0.001
I/II
III/IV
43
37
116.7 (29.2–466.1)
137.8 (32.4–585.4)
< 0.001
< 0.001
0.059
VIM (promoter) Lu, 2014 [49] China CRC
Cn
56
40
MSP 4.0 (1.4–10.9) 0.006 I/II
III/IV
32
24
3.9 (1.3–11.9)
4.1 (1.2–13.3)
0.015
0.018
0.938
VIM (promoter) Itzkowitz, 2008 [39] USA CRC
Cn
42
241
MSP 19.6 (8.5–45.2) < 0.001 I
II
III
IV
11
14
14
3
46.1 (5.7–369.3)
27.6 (6.0–128.0)
8.3 (2.7–26.0)
31.9 (1.6–629.7)c
< 0.001
< 0.001
< 0.001
0.001
0.333e
VIM (exon 1) Chen, 2005 [41] USA CRC
Cn
94
198
MSP 7.5 (4.1–13.9) < 0.001 I/II
III/IV
60
34
6.8 (3.4–13.6)
8.9 (3.9–20.1)
< 0.001
< 0.001
0.533f
WIF-1 (promoter) Zhang, 2014 [50] China NAA
AA
Ad
CRC
Cn
20
15
35
48
30
MSP 15.6 (1.7–140.2)
33.1 (3.5–310.3)
24.4 (3.0–199.7)
44.3 (5.6–352.8)
0.003
< 0.001
0.000
< 0.001
I/A
II/B
III/C
IV/D
7
20
14
7
38.7 (3.2–467.8)
67.7 (7.4–617.5)
29.0 (3.1–275.7)
38.7 (3.2–467.8)
0.000
< 0.001
0.000
0.000
0.661e
  1. Notes: Stages I/II/III/IV as per Union for International Cancer Control (UICC) classification and stages A/B/C/D as per Dukes classification. Bold fonts represent results from validation set (non-bold fonts represent results without validation)
  2. Ref. reference, No. number, DNAm DNA methylation, MSP methylation-specific polymerase chain reaction, qMSP quantitative methylation-specific real-time polymerase chain reaction, n-MSP nested methylation-specific polymerase chain reaction, Hi-SA high-sensitivity assay for bisulfite DNA, LTE linear target enrichment, MSRH methylation-specific reverse hybridization, NAA non-advanced adenoma, AA advanced adenoma, Ad adenoma, Cn control
  3. aStatistical significance for OR
  4. bStatistical significance for association between methylation level and CRC stage
  5. cCalculated using Haldane–Anscombe correction (0.5 added to each cell) [53, 54]
  6. dAs reported in the article
  7. eCalculated using Fisher’s exact test
  8. fCalculated using chi-square test
  9. gModel adjusted for age and sex
  10. hSum of methylation + stool samples divided by stages is not equal to the total number of methylation + CRC stool samples