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Table 4 Gene-specific methylation in serum or plasma DNA in breast cancer cases and controls investigated in more than one study

From: Blood-based DNA methylation as biomarker for breast cancer: a systematic review

Gene

Author, year [ref]

Sample

Assay (value)

Case no./control no.

Case age/control age (y)b

Meth (case)

Meth (control)

p value

Main findings

RASSF1A

Kloten V, 2013 [58]

Serum

MS-PCR (%)

136/135

33–86/33–86

47.1

25.9

0.004

Higher frequency of methylated RASSF1A was observed in eight studies. Studies by Zmetakova I et al. and Brooks JD et al. reported no significant differences in methylation of RASSF1A between cases and controls

 

Zmetakova I, 2013 [42]

Plasma

Pyrosequencing (mean ± SD)

34/50

41–90/20–78

2.85 ± 3.13

4.02 ± 6.62

0.404

 

Ahmed IA, 2010 [55]

Serum

MSP (%)

26/12

35–73/35–73

69

<10

–

 

Brooks JD, 2010 [56]d

Serum

QMSP (%)

50/99

52/51.8

22

17.2

>0.05

 

Kim JH, 2010 [57]

Serum

QMSP (%)

119/125

51/51

32.8

4.8

0.004

 

Yazici H, 2009 [46]d

Plasma

MSP (%)

61/39

na/na

18

5

–

 

Hoque M, 2006 [44]

Plasma

QMSP (%)

47/38

44.9/37.3

32

5

0.002

 

Van der Auwera I, 2009 [52]

Serum

QMSP (%)

79/19

62/39

35

0

0.002

 

Papadopoulou E, 2006 [45]

Plasma

Methylight (%)

50/14

na/na

26

0

<0.05

 

Dulaimi E, 2004 [50]

Serum

MSP (%)

34/20

57.4/57.4

56

0

<0.05c

APC

Swellam M, 2015 [59]

Serum

MS-PCR (%)

121/66

43/40

93.4

0

<0.0001

Five out of these seven studies reported higher frequency of methylated APC in BC patients. Studies by Zmetakova I et al. and Brooks JD et al. reported no significant differences in methylation of APC between cases and controls.

 

Zmetakova I, 2013 [42]

Plasma

Pyrosequencing (mean ± SD)

34/50

41–90/20–78

4.41 ± 7.81

2.53 ± 1.56

0.06

 

Radpour R, 2011 [47]

Plasma

EpiTyper assay (mean)

36/30

67/na

0.39b

0.19b

<0.0001

 

Brooks JD, 2010 [56]d

Serum

QMSP (%)

49/96

52/51.8

2

4.2

>0.05

 

Hoque M, 2006 [44]

Plasma

QMSP (%)

47/38

44.9/37.3

17

0

0.008

 

Van der Auwera I, 2009 [52]

Serum

QMSP (%)

79/19

62/39

29

5

0.03

 

Dulaimi E, 2004 [50]

Serum

MSP (%)

34/20

57.4/57.4

29

0

<0.05c

ESR1

Zmetakova I, 2013 [42]

Plasma

Pyrosequencing (mean ± SD)

34/50

41–90/20–78

4.18 ± 4.07

5.24 ± 4.33

0.338

Only one study (Matinez-Galan, J) reported higher methylation levels of ESR1 in BC patients. Others observed no significant methylation differences.

 

Zurita M, 2010 [54]

Serum

QMSP (%)

77/34

na/na

0.005b

0.085b

>0.05

 

Van der Auwera I, 2009 [52]

Serum

QMSP (%)

79/19

62/39

20

10.5

0.33

 

Martinez-Galan J, 2008 [51]

Serum

MSP (%)

106/74

58/42

0.11b

0.02b

0.011

RARB

Swellam M, 2015 [59]

Serum

MS-PCR (%)

121/66

43/40

95.9

0

<0.0001

Higher frequency of methylated RARB was observed except the study conducted by Brooks JD et al.

 

Brooks JD, 2010 [56]d

Serum

QMSP (%)

45/88

52/51.8

6.7

1.1

>0.05

 

Kim JH, 2010 [57]

Serum

QMSP (%)

119/125

51/51

86.6

6.4

<0.001

 

Hoque M, 2006 [44]

Plasma

QMSP (%)

47/38

44.9/37.3

26

8

0.03

GSTP1

Radpour R, 2011 [47]

Plasma

EpiTyper assay (mean)

36/30

67/na

0.52b

0.39b

0.003

Two studies reported higher methylation level (Radpour R et al., 2011) or frequency (Hoque M et al., 2006) of GSTP1 in BC patients. Study by Brooks.J.D observed no significant differences.

 

Brooks JD, 2010 [56]d

Serum

QMSP (%)

50/99

52/51.8

4

7.1

>0.05

 

Hoque M, 2006 [44]

Plasma

QMSP (%)

47/38

44.9/37.3

26

0

0.0008

SFN

Zurita M, 2010 [54]

Serum

QMSP (%)

77/34

na/na

0.002b

0.1b

<0.001

Both studies reported higher methlyation of SFN in BC patients.

 

Martinez-Galan J, 2008 [51]

Serum

MSP (%)

106/74

58/42

0.20b

0.075b

0.0047

BRCA1

Liu LM, 2015 [60]

Serum

Bisulfite sequencing PCR and MS-HRM (%)

36a/30a

na/na

10

1.7

<0.05

Both studies reported higher methlyation of BRCA1 in BC patients

 

Radpour R, 2011 [47]

Plasma

EpiTyper assay

36/30

67/na

0.58b

0.30b

<0.0001

CST6

Chimonidou M, 2013 [49]

Plasma

MSP (%)

73/37

na/na

16.4

0

 

ChimonidouM et al. reported that CST6 promoter is highly methylated in cfDNA of breast cancer patients, but not in healthy individuals. Radpour R et al. observed higher methlytion level of CST6 in BC patients.

 

Radpour R, 2011 [47]

Plasma

EpiTyper assay (mean)

36/30

67/na

0.62b

0.42b

<0.002

DAPK

Ahmed IA, 2010 [55]

Serum

MSP (%)

26/12

35–73/35–73

88

<10%

<0.05

Higher frequency of methylated DAPK in patients was observed in both studies.

 

Dulaimi E, 2004 [50]

Serum

MSP

34/20

57.4/57.4

35

0

<0.05c

TIMP3

Zmetakova I, 2013 [42]

Plasma

Pyrosequencing (mean ± SD)

34/50

41–90/20–78

3.97 ± 8.43

3.92 ± 4.54

0.697

Zmetakova I et al. reported no significant difference in methylation of TIMP3 between patients and healthy controls. Radpour R et al. observed higher methylation level of TIMP3 in BC patients.

 

Radpour R, 2011 [47]

Plasma

EpiTyper assay

36/30

67/na

0.60b

0.50b

<0.0001

  1. MSP methylation-specific PCR, QMSP quantitative methylation-specific PCR, MS-HRM methylation-sensitive high-resolution melting, na not available
  2. aAge indicates mean age or range
  3. bData was extracted from scatter plots or boxplots in the article
  4. c p values were calculated by Fisher’s exact test
  5. dNested case–control study; the others are case–control study