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Table 1 Diagnostic methylated ctDNA in colorectal cancer patients

From: Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction

Gene Country No. of cases No. of controls Cases characteristics Sample type Technology used AUC (p-value) Sensitivity (%) Specificity (%) References
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]
  1. *(cg16959747, cg10673833, cg21939215, cg24067911, cg17494199, cg23678254, cg10428836, cg10493436, cg25459300), **(FAM123A, GLI3, PPP1R16B, SLIT3, TMEM90B), ***(FER1L4, VAV3, CHST2, DTX1, PDGFD, SFMBT2, QKI, ZNF568, ANKRD13B, ZNF671, CNNM1, GRIN2D, JAM3)
  2. A, adenoma; AA, advanced adenoma; APL, advanced precancerous lesions; AQAMA, absolute quantitaive analysis of methylates alleles; AUC, area under curve; BL, benign lesions; CC, combined cohort; CMI, cumulative methylation index; CRC, colorectal cancer; ddMethyLight, droplet digital MethyLight; dd-PCR, droplet digital PCR; dd-QMSP, droplet digital quantitative methylation-specific PCR; GID, gastrointestinal diseases; HGD, high grade dysplasia; HM, heavy methyl quantitative real-time PCR; HPP, hyperplastic polyps; HRA, high-risk adenoma; INF, inflammation; LRA, low-risk adenoma; MCTA-Seq, methylated CpG tandem amplification and sequencing; MSRE-PCR, methylation sensitive restriction enzyme and multiplex PCR; NED, no evidence of disease; NAA, non-advanced adenomas; N, normal; PL, precancerous lesions; P, polyps; QM-MSP, quantitative multiplex methylation-specific PCR; SA, serrated adenoma; SSP, serrated sessile adenomas/polyps; SP, small polyps; TELQAS, target enrichment long-probe quantitative-amplified signal TA, tubular adenoma; TVA, tubulovillous adenoma; VA, villous adenoma; TC, test cohort; VC, validation cohort