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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
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Clinical Epigenetics

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