Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review

Raut, Janhavi R.; Guan, Zhong; Schrotz-King, Petra; Brenner, Hermann

doi:10.1186/s13148-020-00904-7

Clinical Epigenetics

Table 3 Overall and stage-wise diagnostic performance of individual DNA methylation markers in stool for detection of colorectal neoplasms

From: Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review

Gene	First author, year, Ref. No.	Country	Study group	No.	DNAm assay	Sn (%)	AUC (95%CI), p-value	CRC stage	No.	Stage-specific Sn (%)	Specificity (%)
CDKN2A (promoter)	Abbaszadegan, 2007 [42]	Iran	CRC Cn	25 20	MSP	20		II/B III/C	14 5	7 60	100
COL4A1 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	58 89	0.76 (0.69–0.84) 0.97 (0.94–0.99)	I/II III/IV	43 37	88 89	88
COL4A2 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	49 93	0.78 (0.70–0.85) 0.97 (0.94–0.99)	I/II III/IV	43 37	91 95	92
FBN1 (promoter)	Guo, 2013 [25]	China	CRC Cn	75 30	MSP	72		I II III IV	12 30 30 3	92 63 73 67	93
FBN1 (promoter)	Li, 2015 [27]	China	CRC Cn	89 30	MSP	71*		I/A II/B III/C	17 36 36	77* 69* 94*	93
GATA4 (promoter)	Hellebrekers, 2009 [37]	Netherlands	CRC Cn	28 45	qMSP	71	0.81 (0.70–0.89)	I/II III/IV	18 10	55 100	84
GATA4 (promoter)	Hellebrekers, 2009 [37]	Netherlands	CRC Cn	47 30	qMSP	51		I/II III/IV	29 17	48 59	93
GATA4 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	43		I/II III/IV	32 24	38 50	95
GATA5 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	84		I/II III/IV	32 24	78 92	83
HIC1 (promoter)	Lenhard, 2005	Germany	AA CRC Cn	13 26 50	MSP	31 42		I/II III/IV	6 20	67 25	98
ING1 (promoter)	He, 2014 [26]	China	AA CRC Cn	27 61 20	n-MSP	63 74		A/B C/D	33 28	70 79	95
ITGA4 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	42 83	0.74 (0.66–0.81) 0.95 (0.92–0.99)	I/II III/IV	43 37	81 84	96
miR-34a (promoter)	Wu, 2014 [36]	China	CRC Cn	82 40	MSP	77		I	13	62	95
miR-34b/c (promoter)	Wu, 2014 [36]	China	CRC Cn	82 40	MSP	94		I	13	85	100
miR-34b/c (promoter)	Kalimutho, 2011 [33]	Italy	0/ AA CRC Cn	5 23 39	MSP	60 78		I II III	2 6 3	100 50 67	87
NDRG4 (promoter)	Xiao , 2015 [32]	China	CRC Cn	84 16	n-MSP	76		I/II III/IV	48 36	81 69	89
NDRG4 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	29		I/II III/IV	32 24	22 38	98
OSMR (promoter)	Kim, 2009 [24]	Belgium	CRC Cn	69 81	qMSP	38		I II III IV	18 27 18 6	11 56 44 17	95
RASSF2: Region 1 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	0 19 9 27		I/II III/IV	40 44	25 30	97
RASSF2: Region 2 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	4 7 5 36		I/II III/IV	40 44	23 48	97
SDC2	Niu, 2017 [51]	China	AA CRC Cn	122 196 179	qMSP	58 81	0.79 (0.74–0.85) 0.92 (0.89–0.95)	I/II III/IV	87 109	84 79	93
SDC2	Han, 2019 [28]	South Korea	NAA 0/ AA Ad CRC Cn	41 6 47 242 245	LTE-qMSP	24 83 32 90	0.90 (0.88–0.93)^#	I II III IV	55 70 96 21	86 91 90 100	90
SDC2	Oh, 2017 [35]	South Korea	NAA CRC Cn	21 50 22	LTE-qMSP	33 90	0.93 (0.85–0.98)	I II III IV	12 17 10 11	83 88 90 100	91
SFRP2 (promoter)	Kriegshäuser, 2017 [38]	Austria	CRC Cn	18 22	MSRH	61		I II	2 16	100 56	86
SFRP2 (promoter)	Zhang, 2014 [50]	China	NAA AA Ad CRC Cn	20 15 35 48 30	MSP	55 80 66 56		I/A II/B III/C IV/D	7 20 14 7	71 50 57 57	100
SFRP2 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	57		I/II III/IV	32 24	50 67	90
SFRP2 (promoter)	Tang, 2011 [47]	China	AA CRC Cn	63 169 30	MSP	46 84		I/II III/IV	99 70	83 86	93
SFRP2: Region 1 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	14 30 21 57		I/II III/IV	40 44	58 57	97
SFRP2: Region 2 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	14 22 18 38		I/II III/IV	40 44	38 39	96
SFRP2 (promoter)	Wang, 2008 [43]	China	AA CRC Cn	34 69 30	qMSP (Methy-Light)	62 87		I/II III/IV	30 39	83 90	93
SNCA (promoter)	Yang, 2017 [52]	China	NAA AA Ad CRC Cn	36 13 49 31 64	qMSP	72 77 76 84	0.77, < 0.001 0.84, < 0.001	I/II III/IV	17 13	82 85	75
SNCA (promoter)	Li, 2015 [27]	China	CRC Cn	89 30	MSP	70*		I/A II/B III/C	17 36 36	65* 81* 67*	100
SPART (promoter)	Zhang, 2013 [48]	China	CRC Cn	96 30	MSP	80		I	21	71	100
TLX2 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	55 89	0.79 (0.71–0.86) 0.96 (0.92–0.99)	I/II III/IV	43 37	81 97	96
VIM (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	41		I/II III/IV	32 24	41 42	85
VIM (promoter)	Itzkowitz, 2008 [39]	USA	CRC Cn	42 241	MSP	81		I II III IV	11 14 14 3	91 86 64 100	82
VIM (exon 1)	Chen, 2005 [41]	USA	CRC Cn	94 198	MSP	46		I/II III/IV	60 34	43 50	90
WIF-1 (promoter)	Zhang, 2014 [50]	China	NAA AA Ad CRC Cn	20 15 35 48 30	MSP	35 53 46 60		I/A II/B III/C IV/D	7 20 14 7	57 70 50 57	97

Notes: Stages I/II/III/IV as per UICC classification and stages A/B/C/D as per Dukes classification. Bold fonts represent results from validation set (non-bold fonts represent results without validation)
Ref. reference, No. number, DNAm DNA methylation, MSP methylation-specific polymerase chain reaction, qMSP quantitative methylation-specific polymerase chain reaction, n-MSP nested methylation-specific polymerase chain reaction, Hi-SA high-sensitivity assay for bisulfite DNA, LTE linear target enrichment, MSRH methylation-specific reverse hybridization, NAA non-advanced adenoma, AA advanced adenoma, Ad adenoma, Cn control
*The sum of methylation + stool samples divided by stages is not equal to the total number of methylation + CRC stool samples
^#For a combined group including three AA (stage 0 CRC) cases along with CRC cases

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ISSN: 1868-7083

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