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Table 3 Gene-specific methylation biomarkers investigated in plasma or serum from OC and controls, including methods, methylation frequency, and performance for early diagnosis of OC

From: Early diagnosis of ovarian cancer based on methylation profiles in peripheral blood cell-free DNA: a systematic review

Gene

Author (et al.)

Method

Case/control

Meth OC

Meth control

Sensitivity % (95% CI)

Specificity % (95% CI)

APC

de Caceres [18]

MSP

50/10b/20h (T)

N/A

N/A

N/A

N/A

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

Tomeva [45]

Real-Time qPCR

19/8h (T)

N/A

N/A

N/A

N/A

BRCA1

de Caceres [18]

MSP

50/10b/20h (T)

N/A

N/A

N/A

N/A

Melnikov [20]

MSRE PCR/microarray

33/33h (T)

31/33*

17/33*

93.9* (79.8–99.3)

48.5* (30.8–66.5)

Liggett [24]

MSRE PCR/microarray

30/30b/30h (T)

N/A

N/A

N/A

N/A

Wang [26]

Real-time qMSP

60/30b/30h (T)

N/A

N/A

N/A

N/A

Kumar [37]

MSP

53/12b/15h (T)

33/53

6/12b

0/15h

62.3* (47.9–75.2)

77.8* (57.7–91.4)

Tserpeli [43]

Real-time qMSP

84/49/27h (T)

10/82

10/48

0/27

12.2 (6.01–21.3)

20.8 (10.5–35.0)

100 (87.2–100)

CDH1

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

Dvorská [36]

Pyrosequencing

33/5b/9h (T)

N/A

N/A

N/A

N/A

DAPK

Häfner [23]

MSP/Sanger sequencing

32/30b/20h (T)

13/23 †

5/21b

4/8h †

56.5* (34.5–76.8)

69.0* (49.2–84.7)

Swellam [32]

MSP

90/50b/30h (T)

87/90

20/50b/0/30h

96.7 (90.6–99.3)

75.0 (64.1–84.0)

HIC1

Melnikov [20]

MSRE PCR/microarray

33/33h (T)

26/33*

17/33*

78.8* (61.1–91.0)

48.5* (30.8–66.5)

Singh [39]

Real-time qMSP

45/25h (T)

32/45

0/25

71.1 (55.7–83.6)

100 (86.3–100)

Singh [42]

Real-time qMSP, Multiplex

45/25h â–  (T)

32/45

0/25

71.1 (55.7–83.6)

100 (86.3–100)

HOXA9

Singh [39]

Real-time qMSP

45/25h (T)

28/45

0/25

62.2 (46.5–76.2)

100 (86.3–100)

Faaborg [40]

Methylation-specific Droplet digital PCR

79/64h (T)

47/79

3/64*

59.5 (47.9–70.4)

95.3 (86.9–99.0)

Singh [42]

Real-time qMSP, Multiplex

45/25h â–  (T)

28/45

0/25

62.2 (46.5–76.2)

100 (86.3–100)

OPCML

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

Zhou [29]

MSRE PCR

45/20h (T)

36/45

0/20

80.0 (65.4–90.4)

100 (83.2–100)

Wang [30]

MSP, Nested multiplex

71/43b/80h (T)

N/A

N/A

N/A

N/A

Swellam [32]

MSP

90/50b/30h (T)

88/90

24/50b

0/30h

97.8 (92.2–99.7)

70.0 (58.7–79.7)

Wang [33]

MSP, Nested

71/43b/80h ‡ (T)

64/71

10/123*

90.1 (80.7–95.9)

91.9 (85.6–96.0)

PAX1

Su [19]

MSP

26/20b (T)

5/26

0/20b

19.2* (6.55–39.4)

100* (83.2–100)

Dvorská [36]

Pyrosequencing

33/5b/9h (T)

N/A

N/A

N/A

N/A

PGR

Melnikov [20]

MSRE PCR/microarray

33/33h (T)

27/33*

15/33*

81.8* (64.5–93.0)

54.6* (36.4–71.9)

Liggett [24]

MSRE PCR/microarray

30/30b/30h (T)

N/A

N/A

N/A

N/A

RASSF1A

de Caceres [18]

MSP

50/10b/20h (T)

N/A

N/A

N/A

N/A

BonDurant [21]

Real-time qMSP

21/7h (T)

18/21

N/A

85.7* (63.7–97.0)

N/A

Liggett [24]

MSRE PCR/microarray

30/30b/30h (T)

N/A

N/A

N/A

N/A

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

Giannopoulou [31]

Real-time qMSP/MS-HRMA

59/51h (T)

15/59

0/51

25.4* (15.0–38.4)

100* (93.0–100)

Kumar [37]

MSP

53/12b/15h (T)

20/53

2/12b/0/15h

37.7* (24.8–52.1)

92.6* (75.7–99.1)

Tomeva [45]

Real-Time qPCR

19/8h (T)

N/A

N/A

N/A

N/A

RUNX3

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

Wang [30]

MSP, Nested multiplex

71/43b/80h (T)

N/A

N/A

N/A

N/A

SFRP5

Su [19]

MSP

26/20b (T)

4/26

2/20b

15.4* (4.36–34.9)

90.0* (68.3–98.8)

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

SOX1

Su [19]

MSP

26/20b (T)

15/26

3/20b

57.7* (36.9–76.7)

85.0 (62.1–96.8)

Singh [42]

Real-time qMSP/, Multiplex

45/25h â–  (T)

24/45

1/25

53.3 (37.9–68.3)

96.0 (79.7–99.9)

TFPI2

Zhang [27]

MSP, Nested multiplex

87/53b/62h (T)

39/29b (V)

N/A

N/A

N/A

N/A

Wang [30]

MSP, Nested multiplex

71/43b/80h (T)

N/A

N/A

N/A

N/A

ZNF154

Miller [38]

DREAMing

26/41h (T)

8/12h (V)

N/A

N/A

65.0 Epiclass/54.0 Mean Meth

91.7 Epiclass/

83.3 Mean Meth

83.0 Epiclass/63.0 Mean Meth

100 Epiclass/66.7 Mean Meth

Miller [41]

DREAMing

38/20h (T)

33/38*

4/20*

86.8 (71.9–95.6)

80.0 (56.3–94.3)

  1. Only gene-specific methylation biomarkers reported in more than one study are included. 95% exact confidence intervals (CI) have been calculated when data were available
  2. b benign, bl borderline tumor, h healthy, Meth methylated, MSP methylation-specific-PCR, MSRE methylation-sensitive restriction enzyme, MS-HRMA methylation-sensitive high resolution melting analysis, N/A not available, PCR polymerase chain reaction, qMSP quantitative methylation-specific PCR, qPCR quantitative PCR, TELQAS Target Enrichment Long-probe Quantitative Amplified Signal, T training/test cohort, V validation cohort
  3. *Extrapolated calculations based on available data
  4. †The number of included methylation frequencies varies to the cohort size as only samples with beta-actin amplification were analyzed further
  5. ‡Appear to be use of cohort and/or data from Wang et al. [30]
  6. â– Reuse of data from Singh et al. [39]