DNA Methylation as a Noninvasive Epigenetic Biomarker for the Detection of Cancer

Table 1

Noninvasive epigenetic DNA methylation biomarkers used in cancers.

Methylated gene	Marker (Dx/Px)	Cancer	DNA source	Cohort	Method	Accuracy (statistic of individual gene)	Ctrl†	Accuracy of panel including methylated gene		Ref
								Genes (n)	Statistic
ARF	Dx	Bladder	Urine sediment	15 BlCa, 25 NC	qPCR	†27%, (4/15)	100% -ve	4	∆82%/96%	[58]
APC	Px	Prostate	Urine	665 men with elevated PSA	qPCR	—	—	2	—	[10]
BCL	Dx	Bladder	Urine sediment	37 BlCa, 20 NC	MethyLight	†65% (24/37)	100% -ve	3	†78% (29/37)	[45]
CDH13	Px	Prostate	Serum	98 PCa, 47 NC	qMSP	†45%, 44/98	100% -ve	—	—	[52]
CDKN2A	Dx	Bladder	Urine sediment	15 BlCa, 25 NC	qPCR	†47%, 7/15	100% -ve	4	∆82%/96%	[58]
DAPK	Dx	Bladder	Urine sediment	37 BlCa, 20 NC	MethyLight	†22% (8/37)	100% -ve	3	†78% (29/37)	[45]
ERα	Dx	Prostate/breast (primary)	Serum	16 PCa/120 BCa, 100 BN	qMSP	†13% (2/16), †72%	—	3	∆75%/70%	[21, 77]
ERβ	Dx	Prostate	Serum	16 PCa	qMSP	†13% (2/16)	—	3	∆75%/70%	[21]
FBN1	Dx	Colorectal	Stool	89 CRC, 30 NC	qMSP	†70.8% (63/89	93% -ve	2	∆84.3%/93.3%	[35]
FBN2	Dx	Colorectal (primary)	Serum	78 CRC	qMSP	†8% (4/49)		—	—	[62]
GSTP1	Dx, Px	Bladder/prostate/castrate-resistant prostate/breast	Urine sediment/urine/plasma/serum	15 BlCa, 25 NC/665 men w/ elevated PSA/34 PCa/24 PCa, 8HGPIN, BN/75 CR-PCa/120 BCa/101 BCa (primary), 58 BCa (secondary), 87 healthy	qPCR, OS-MSP	†47% 7/15/†4% 4/101/†3% 1/34/†67% 50/75	100% -ve	4, 2, 3, 3, 3	∆82%,96%/−/†82% (28/34)/∆75%/98%/†6% 7/120/†22% 22/101	[10, 41, 43, 44, 53, 55, 58]
FHIT	Dx	Ductal breast cancer	Serum	36 BCD, 30NC, 30 BN	qMSP and high-resolution melting curve analysis	64%	35% NC, 64% BC	—	—	[76]
hMLH1	Dx	Breast	Serum	268 BCa, 245 NC, 236 BN	MethyLight	†28% 75/268	85.71% -ve NC, 77.97% -ve BN	6	AUC = 0.727 (BCa versus NC), AUC = 0.789 (BCa versus BN)	[8]
HLTF	Px	Colorectal	Serum	106 CRC	MethyLight	—	—	—	—	[20]
HOXD13	Dx	Breast	Serum	268 BCa, 245 NC, 236 BN	MethyLight	†37/268	97.55% -ve NC, 99.58% -ve NC	6	AUC = 0.727 (BCa versus NC), AUC = 0.789 (BCa versus BN)	[8]
MCAM	Dx (early)	Prostate	Serum	16 PCa	qMSP	†46% (12/16)	—	3	∆75%/70%	[21]
MGMT	Dx	Bladder/lung	Urine sediment/bronchial washing	15 BlCa, 25 NC/8 SCLC	qPCR/MSP	†27% 4/15, †75% 6/8	100% -ve	4	∆82%/96%	[52, 73]
NID2	Dx	Bladder (primary)	Urine	157 BlCa, 339 urological disorder	qMSP	∆94%, 91%	—	2	†94% (466/496)	[84]
P16	Dx	Breast	Serum	268 BCa, 245 NC, 236 BN	MethyLight	†22% 60/268	83.27% -ve NC, 84.32% -ve BN	6	AUC = 0.727 (BCa versus NC), AUC = 0.789 (BCa versus BN)	[8]
PCDHGB7	Dx	Breast	Serum	268 BCa, 245 NC, 236 BN	MethyLight	†148/268	52.65% -ve NC, 54.66% -ve BN	6	AUC = 0.727 (BCa versus NC), AUC = 0.789 (BCa versus BN)	[8]
PCDH10	Px	Prostate	Serum	171 primary PCa, 65 BN	qMSP	†51.5% (88/171)	100% -ve	—	—	[22]
PCDH17	Dx	Bladder	Urine sediment	58 BlCa, 20 IUC, 20 KCa, 20 PCa	qMSP	AUC = 0.813	75% -ve	2	∆90%/93.96%	[24]
PHACTR3	Dx	Colorectal	Stool	11 CRC, 20 NC	qMSP	†44% 4/9	100% -ve	—	—	[85]
POU4F2	Dx	Bladder	Urine sediment	58 BlCa, 20 IUC, 20 KCa, 20 PCa	qMSP	AUC = 0.921	94% -ve	2	∆90%/93.96%	[24]
TERT	Dx	Bladder	Urine sediment	37 BlCa, 20 NC	MethyLight	†51% (18/37)	100% -ve	3	†78% (29/37)	[45]
TMEFF2	Dx	NSCLC	Serum	316 NSCLC, 50 NC		†9.2% 29/36	100% -ve	—	—	[70]
RARB	Dx	Prostate	Urine sediment	34 PCa	qMSP	†44% (15 of 34)		3	†82%(28/34)	[55]
RARβ2	Dx	Breast	Serum	120 BCa//101 BCa (primary), 58 BCa (secondary), 87 healthy	OS-MSP	−, †12% 12/101	—	3, 3	†6% 7/120/†22% 22/101	[43, 44]
RASSF1	Dx	Prostate	Urine sediment	34 PCa	qMSP	†71% 24/34		3	†82% (28/34)	[55]
RASSF1a	Dx, Px	Breast/lung/ovarian	Serum	268 BCa, 245 NC, 236 BN/101 BCa (primary), 58 BCa (secondary), 87 healthy /120 BCa/90 LCa/59 HGSC	qMSP/OS-MSP/MSP, MS-HRMA	†17% 46/268, †7% 7/101 †33.8% 27/80, †25.4% 15/59	89.67% -ve NC, 91.95% -ve BN/100% -ve	6, 3	AUC = 0.727 (BCa versus NC), AUC = 0.789 (BCa versus BN)/†6% 7/120/†22% 22/101	[8, 43, 44]
RASSF2A	Dx	Ovarian	Plasma	47 EOC, 14 BN, 10 NC	MSP	†36.2% 17/47	100% -ve BN, 100% -ve NC	—	—	[82]
SEPT9	Px	Colorectal	Serum	150 CRC, 60 CRC	qMSP, Abbott MS-9 reagent kit and PCR	−, ∆47%/89%	—	—	—	[34, 63]
SFN	Dx	Breast	Serum	268 BCa, 245 NC, 236 BN	MethyLight	†74% 197/268	85.71%-ve NC, 77.97% -ve BN	6	AUC = 0.727 (BCa versus NC), AUC = 0.789 (BCa versus BN)	[8]
SNCA	Dx	Colorectal	Stool	89 CRC, 30 NC	qMSP	†70% 62/89	100% -ve	2	∆84.3%/93.3%	[35]
SST	Px	Colorectal	Serum	165 CRC	—	—	—	—	—	[59]
TAC1	Px	Colorectal	Serum	150 CRC	qMSP	—	—	—	—	[63]
TWIST1	Dx	Bladder (primary)	Urine	157 BlCa, 339 urological disorder	qMSP	∆88%, 94%	—	2	†94% (466/496)	[84]
VIM	Dx	Colorectal	Serum	44 CRC, 239 CRC	qMSP	†9% 4/44, †33% 78/239	—	—	—	[61, 65]

Dx: diagnosis; Px: prognosis; BN: benign controls; NC: noncancer controls; ∆: sensitivity/specificity; †: % of samples detected; AUC: area under the curve (0-1) for ROC (receiver operating characteristic); BlCa: bladder cancer; BCa: breast cancer; BCD: breast ductal carcinoma; CR-PCa: castrate resistant prostate cancer; CRC: colorectal cancer; HGSC: high-grade serous ovarian cancer; IUC: infected urinary calculi: KCa: kidney cancer: LCa: lung cancer, NSCLC: non-small-cell lung cancer; PCa: prostate cancer; SCLC: small cell lung cancer.