Table 1 Diagnostic methylated ctDNA in colorectal cancer patients

SEPT9

China

117 CRC, 45 AA, 50 NAA

70 N

I (20), II (47), III (35), IV (4)

Plasma

Epi proColon 2.0

CRC (73.2), A (< 27.6), NAA (26.5), I (52.6), II (84.8), III (78.8), IV (100)

CRC (66.7)

[18]

SEPT9

China

63 CRC, 82 A&P

11 nonCRC GID, 494 NED

Plasma

Epi proColon 2.0

0.835

CRC (73), A&P (17.1), nonCRC GID (18.2)

CRC (94.5), A&P (94.5)

[19]

SEPT9

Singapore

26 CRC

26 N

All stage I

Serum

MethyLight

0.793 (< 0.001)

50

at least 90

[20]

EYA4

0.789 (< 0.001)

57.7

at least 90

TAC1

0.768 (< 0.001)

57.7

at least 90

TAC1 and EYA4

0.821 (< 0.001)

84.6

80.8

TAC1 and SEPT9

0.851 (< 0.001)

73.1

92.3

SEPT9

China

187 CRC, 25 P

109 N

Plasma

MethyLight

CRC (0.777)

CRC (62.6), I–II (57.1), III–IV (69.5), P (12)

91.7

[21]

OSMR

CRC (0.796)

CRC (74.9), I–II (74.4), III–IV (76.8), P (20)

86.2

SEPT9 and OSMR

CRC (77), I–II (78.1), III–IV (76.8), P (28)

81.7

TMEFF2

Germany

133 CRC

179 N

I (20), II (32), III (47), IV (31)

Plasma

HM

0.72

all (30), I (5), II (22), III (34), IV (45)

95

[22]

NGFR

0.7

all (33), I (20), II (25), III (36), IV (36)

95

SEPT9

0.8

all (52), I (30), II (56), III (45), IV (68)

95

SEPT9 and ALX4

Germany

VC: 5 CRC, 49 P

VC: 22 N

VC: UICC I (4), III (1)

Plasma

MethyLight

P (71)

P (95)

[23]

SEPT9

China

98 CRC, 101 A

253 NED

0 (3), I (23), II (31), III (8), IV (2)

Plasma

Epi proColon 2.0

CRC: 0.802, A: 0.532 (< 0.001)

CRC (61.22), A (7.9)

CRC (98.42)

[24]

98 CRC

253 NED, 101 A, 76 nonCRC cancers, 30 INF

61.22

93.7

SEPT9

China

123 CRC

125 N

I (5), II (36), III (58), IV (4)

Plasma

MSP

all: 0.757

all (61.8), I (60), II (52.8), III (63.8), IV (50)

89.6

[25]

SEPT9

Taiwan

51 CRC

9 N

0-II (23), III–IV (28)

Plasma

Abbott MS-9

47

89

[26]

SEPT9

China

85 CRC, 364 A, 216 HPP, 372 GID

324 N

I (9), II (38), III (31), IV (7), SA (36), TA (202), TVA (108), VA (18)

Plasma

Epi proColon 2.0 CE

CRC: 0.887, AA: 0.675, NAA: 0.582, P: 0.555

all (87.1), I (77.8), II (78.9), III (96.8), IV (100), A (38.7), NAA (27.5), AA without HGD (47), AA with HGD (62.5), SA (27.8), TA (28.7), TVA (53.7), VA (83.3)

[27]

SEPT9

China

465 CRC, 164 A, 108 HPP

610 NED

I (52), II (129), III (165), IV (25), SA (15), TA (84), TVA (54), VA (11)

Plasma

Epi proColon 2.0

CRC versus NED: 0.81, CRC versus A/HPP/NED: 0.8, CRC versus A/HPP: 0.78, CRC IV versus I–III: 0.73, VA versus no VA: 0.59, BL versus NED: 0.51

I (53.8), II (80.6), III (77.4), IV (84.2), HPP (9.3), SA (13.3), TA (19), TVA (41.2), VA (66.7)

[28]

SEPT9 (10 subregions)

China

53 CRC, 48 AA, 30 BL

48 N

I (14), II (16), III (9), IV (14)

Plasma

MSP

0.882 (< 0.0001)

all (84.9), I (64.3), II (81.3), III (100), IV (100), AA (23), BL (40)

all (83.3)

[29]

BCAT1

Australia

74 CRC

144 N

I (4), II (28), III (23), IV (8)

Plasma

MSP

CRC (64.9), I (25), II (64), III (65), IV (88)

96.5

[32]

IKZF1

CRC (67.6), I (25), II (57), III (78), IV (100)

95.1

BCAT1 and IKZF1

CRC (77), I (50), II (68), III (87), IV (100)

92.4

BCAT1

Australia, Netherland, Denmark

184 CRC, 337 AA, 279 NAA

820 N

I (41), II (57), III (51), IV (33)

Plasma

MSP

CRC (0.71)

CRC (47.3), AA (8.6), NAA (4.7), I (19.5), II (52.6), III (45.1), IV (75.8)

94.6

[33]

IKZF1

CRC (0.775)

CRC (59.2), AA (8.6), NAA (4.3), I (26.8), II (70.2), III (64.7), IV (69.7)

95.7

IRF4

CRC (0.739)

CRC (50), AA (5.9), NAA (2.9), I (17.1), II (57.9), III (54.9), IV (66.7)

97.8

BCAT1 and IKZF1

CRC (0.808)

CRC (70.1)

91.5

BCAT1/IKZF1/IRF4

CRC (0.82)

CRC (73.9), AA (15.7), NAA (9.3), I (39), II (87.7), III (78.4), IV (84.8)

90.1

SEPT9

China

111 CRC

114 NED

I (13), II (49), III (39), IV (7)

Serum

MSP

0.854

all (73), I (38.5), II (81.6), III (69.2), IV (100)

95.6

[16]

SDC2

0.881

all (71.2), I (53.9), II (67.4), III (79.5), IV (85.7)

95.6

SEPT9 and SDC2

ColoDefense

0.922

all (86.5), I (69.2), II (85.7), III (89.7), IV (100)

92.1

SEPT9

China

117 CRC, 23 AA

166 N, 78 SP

I (20), II (50), III (38), IV (4)

Plasma

MSP

CRC: 0.9, AA: 0.579

all (82.1), I (65), II (84), III (86.8), IV (100), AA (12.1)

95.8, with SP (92.6)

[17]

SDC2

CRC: 0.886, AA: 0.754

all (69.2), I (55), II (74), III (65.8), IV (100), AA (43.5)

95.8, with SP (93.4)

SEPT9 and SDC2

ColoDefense

CRC: 0.941, AA: 0.754

all (88.9), I (80), II (90), III (89.5), IV (100), AA (47.8)

92.8, with SP (87.7)

SDC2

Korea

131 CRC

125 N

Korean: I (11), II (28), III (36), IV (12), European: I (15), II (29)

Serum

MethyLight

0.927 (0.0001)

all (87), I (92.3), II (82.5), III (88.9), IV (91.7)

95.2

[36]

ALX4

Germany

30 CRC

30 N

I (4), II (6), III (17), IV (3)

Serum

MethyLight

0.839

83.3

70

[37]

SFRP1

Hungary

47 CRC, 37 A

37 N

Plasma

MethyLight

CRC: 0.869, A: 0.824 (< 0.0002)

CRC (80.9), A (89.2)

CRC (83.8), A (73)

[38]

SFRP2

CRC: 0.863, A: 0.789 (< 0.0002)

CRC (63.8), A (81.1)

CRC (97.3), A (73)

SDC2

CRC: 0.930, A: 0.859 (< 0.0002)

CRC (87.2), A (73)

CRC (100), A (94.6)

PRIMA1

CRC: 0.822, A: 0.782 (< 0.0002)

CRC (57.4), A (59.5)

CRC (100), A (97.3)

SFRP1/SFRP2/SDC2/PRIMA1

CRC: 0.978, A: 0.937

CRC (91.5), A (89.2)

CRC (97.3), A (86.5)

SFRP2

China

62 CRC, 7 AA

55 N

I (13), II (27), III (17), IV (5)

Serum

MethyLight

0.821

all (69.4), I (46.2), II (74.1), III (70.6), IV (100), AA (42.9)

87.3

[39]

OSMR

Italy

70 CRC

18 A, 36 N

I (11), II (15), III (29), IV (15)

Plasma

MethyLight

CRC versus N: 0.6944, CRC versus A: 0.6472 (0.002)

CRC versus NorA (44.3)

CRC versus N (86.1), CRC versus A (83.3)

[42]

SFRP1

CRC versus N: 0.7952, CRC versus A: 0.7560 (< 0.0001)

CRC versus NorA (62.9)

CRC versus N (91.7), CRC versus A (83.3)

VIM

Germany

81 CRC

110 N

Plasma

Methyl-BEAMing

all: 0.81, Duke's A: 0.77, B: 0.82, C: 0.67, D: 0.95

all S (59), Duke's A&B (52)

93

[43]

B4GALT1

Italy

TC: 20 CRC, VC: 26 CRC

19 N

Plasma

dd-QMSP

TC: 0.750 (0.008)

TC: 50

TC: 100

[45]

WIF1

Korea

243 CRC, 64 A

276 N

I (44), II (199)

Plasma

MSP

0.641

36.7

90.6

[46]

APC, MGMT, RASSF2A, WIF1

CRC: 0.927, A: 0.864

CRC (86.5), A (74.6)

CRC (92.1), A (91.3)

JAM3 or JAMC

China

18 CRC

18 N

I (1), II (4), III (7), IV (3)

Plasma

MSP

0.8611 (< 0.001)

[47]

PCDH18

China

20 CRC

20 N

Plasma

MSP

0.85 (< 0.05)

[48]

NEUROG1

Germany

45 CRC

16 N

UICC I (11), II (9), III (7), IV (18) (marker comparison set)

Serum

MethyLight

55.5

81.3

[49]

ALX4

46.6

66.3

SEPT9

46.6

81.3

VIM

41.1

60

NEUROG1

92 CRC

45 N

UICC I (27), II (70) (test set)

0.73 (< 0.0001)

UICC I (51.9), II (64.3)

91.1

NDRG4

Germany

TC: 154 CRC, VC: 66 CRC

TC: 444 N, VC: 240 N

TC: I (43), II (44), III (46), IV (21), VC: I (27), II (15), III (20), IV (4)

Plasma

MSP

TC: 0.61

TC: all (27), I (16), II (11), III (35), IV (62)

TC (95)

[50]

GATA5

TC: 0.59

TC: all (18), I (14), II (9), III (17), IV (47)

TC (99)

FOXE1

TC: 0.7

TC: all (46), I (35), II (43), III (50), IV (67)

TC (93)

SYNE1

TC: 0.72

TC: all (47), I (28), II (52), III (46), IV (76)

TC (96)

SYNE1 and FOXE1

TC: all (56), I (42), II (57), III (59), IV (81), VC: all (58), I (37), II (87), III (55), IV (100)

TC (90), VC (91)

C9orf50

Netherlands

75 CRC

66 N

I (19), II (24), III (31), IV (1)

Plasma and serum

Digital MethyLight

plasma: 0.7, serum: 0.69

[51]

THBD

plasma: 0.8, serum: 0.82

plasma (71)

plasma (80)

C9orf50 and THBD

plasma: 0.8, serum: 0.83

HIC

Italy

30 CRC

30 N

I (11), II (19)

Plasma

MSRE-PCR

0.858

76.67

83.3

[52]

CYCD2

0.8322

70

73.3

VHL

0.703

75.8

66.67

HIC/CYCD2/VHL

30 CRC + VC: 10 CRC

30 N + VC: 10 N

0.9379, VC: 0.9

82.76, VC (70)

93.3, VC (90)

LINE-1

Japan

114 CRC

53 N

I–II (57), III–IV (57)

Plasma

AQAMA-real time PCR

all: 0.81, I–II: 0.79, III–IV: 0.83 (< 0.0001)

all (65.8), I–II (63.2), III–IV (68.4)

all (90), I–II (90), III–IV (90)

[53]

ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM

Denmark

193 CRC

102 N including 33 with resectable A

Plasma

MSP

all: 0.887, I–II: 0.8775 (= 0.3512)

all (90.7), I–II (88.7)

all (72.5), I–II (73.5)

[13]

80 markers

China

TC: 73 CRC

TC: 70 N

I (18), II (34), III (20), IV (1)

Plasma

MCTA-Seq

0.88

all (75), I (65), II (76), III–IV (81)

94

[56]

VC: 74 CRC

VC: 66 N

I (14), II (33), III (23), IV (4)

0.89

all (79), I (62), II (81), III–IV (85)

86

CC: 147 CRC

CC: 136 N

I (32), II (67), III (43), IV (5)

I–II (74)

I–II (90)

9 markers*

China

TC: 528 CRC

TC: 674 N

I (38), II (139), III (209), IV (406)

Plasma

Deep sequencing

9 markers: 0.96, cg10673833: 0.904

87.5

89.9

[57]

VC: 273 CRC

VC: 347 N

9 markers: 0.96, cg10673833: 0.91

87.9

89.6

cg10673833

29 CRC, 78 APL, 114 NAA, 250 BL

1021 N

dd-PCR

0.9

CRC (89.7), APL (33.3), NAA (21.9), BL (8)

CRC (86.8), APL (66.7), NAA (78.1), BL (92)

CpG sites

China

TC: 149 CRC, VC: 67

TC: 149 N, VC: 74

TC: I (34), II (54), III (35), IV (26), VC: I (17), II (25), III (15), IV (10)

Plasma

MSP

TC: 0.943, VC: 0.934

TC: CRC (88.6), I (79.4), II (88.9), III (91.4), IV (96.2), I–III (87), VC: CRC (83.6), I (70.6), II (88), III (86.7), IV (90), I–III (83.5), TC + VC: CRC (87), I (76.5), II (88.6), III (90), IV (94.4)

TC (89.3), VC (91.9), TC + VC (90.1)

[58]

SEPT9

TC: 0.655, VC: 0.673

TC + VC: CRC (41.2), I (19.6), II (36.7), III (46), IV (75)

TC + VC (90.6)

13 markers ***

Minnesota, USA

97 CRC

200 N

I (11), II (26), III (24), IV (23)

Plasma

TELQAS

all: 0.91

all (77), I (64), II (65), III (71), IV (100)

95

[49]

NPY, PENK, WIF1

France

32 CRC, 26 P

161 N

I–II (6), III–IV (26)

Serum

QM-MSP

CMI 0.62–0.85 (87)

CMI 0.62–0.85 (80)

[60]

CMI 0.94 (78)

CMI 0.94 (90)

CMI 2.01 (59)

CMI 2.01 (95)

5 markers **

Korea

97 CRC

60 N

I (17), II (24), III (33), IV (23)

Plasma

ddMethyLight

I–III (45.9), IV (95.7)

95

[61]