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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