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 2 Overall and stage-wise association of fecal DNA methylation markers with risk 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	N	DNAm assay	OR (95% CI)	p-value^a	CRC stage	N	Stage-specific OR (95% CI)	p-value^a	p-value for methylation-stage association^b
CDKN2A (promoter)	Abbaszadegan, 2007 [42]	Iran	CRC Cn	25 20	MSP	11.0 (0.6–212.1)^c	0.058 0.043^d	II/B III/C	14 5	4.6 (0.2–120.3)^c 57.4 (2.3–1467.3)^c	0.332 0.001	0.037^e
COL4A1 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	10.3 (4.6–22.9) 57.6 (22.1–150.1)	< 0.001 < 0.001	I/II III/IV	43 37	55.5 (17.7–174.0) 60.2 (17.6–206.1)	< 0.001 < 0.001	1.000
COL4A2 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	10.6 (4.3–25.9) 133.9 (43.0–417.2)	< 0.001 < 0.001	I/II III/IV	43 37	105.9 (29.2–383.7) 190.0 (37.5–961.7)	< 0.001 < 0.001	0.815
FBN1 (promoter)	Guo, 2013 [25]	China	CRC Cn	75 30	MSP	36.0 (7.9–164.7)	< 0.001	I II III IV	12 30 30 3	154.0 (12.7–1875.6) 24.2 (4.8–121.6) 38.5 (7.4–199.9) 28.0 (1.7–458.8)	< 0.001 < 0.001 < 0.001 0.003	0.322
FBN1 (promoter)	Li, 2015 [27]	China	CRC Cn	89 30	MSP	33.9 (7.5–152.9)^h	< 0.001	I/A II/B III/C	17 36 36	45.5 (7.4–280.9)^h 31.8 (6.4–157.6)^h 86.8 (15.6–483.6)^h	< 0.001 < 0.001 < 0.001	0.237
GATA4 (promoter)	Hellebrekers, 2009 [37]	Nether-lands	CRC Cn	47 30	qMSP	14.6 (3.1–68.4)	< 0.001	I/II III/IV	29 17	13.1 (2.6–65.3) 20.0 (3.5–112.7)	0.000 < 0.001	0.55^e
GATA4 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	14.3 (3.1–65)	< 0.001	I/II III/IV	32 24	11.4 (2.3–56.0) 19.0 (3.7–97.1)	0.0006 < 0.001	0.35
GATA5 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	24.6 (8.3–72.7)	< 0.001	I/II III/IV	32 24	16.8 (5.2–54.2) 51.9 (9.9–273.2)	< 0.001 < 0.001	0.32 0.274^e
HIC1 (promoter)	Lenhard, 2005	Germany	AA CRC Cn	13 26 50	MSP	21.8 (2.2–218.0) 35.9 (4.3–301.6)	0.001 < 0.001	I/II III/IV	6 20	98.0 (7.2–1330.0) 16.3 (1.8–151.0)	< 0.001 0.0021	0.138^e
ING1 (promoter)	He, 2014 [26]	China	AA CRC Cn	27 61 20	n-MSP	32.3 (3.7–279.3) 53.4 (6.6–432.2)	< 0.001 < 0.001	A/B C/D	33 28	43.7 (5.1–372.8) 69.7 (7.7–631.4)	< 0.001 < 0.001	0.432
ITGA4 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	19.0 (5.5–65.4) 125.7 (34.7–456.2)	< 0.001 < 0.001	I/II III/IV	43 37	116.7 (29.2–466.1) 137.8 (32.4–585.4)	< 0.001 < 0.001	0.779
miR-34a (promoter)	Wu, 2014 [36]	China	CRC Cn	82 40	MSP	63.0 (13.9–285.7)	< 0.001	I	13	30.4 (5.0–185.5)	< 0.001	0.694
miR-34b/c (promoter)	Wu, 2014 [36]	China	CRC Cn	82 40	MSP	1097.2 (59.2–20349.1)^c	< 0.001	I	13	372.6 (16.7–8322.8)^c	< 0.001	0.656
miR-34b/c (promoter)	Kalimutho, 2011 [33]	Italy	0/ AA CRC Cn	5 23 39	MSP	10.2 (1.4–77.0) 24.5 (6.3–95.9)	0.011 < 0.001	I II III	2 6 3	31.4 (1.3–744.4)^c 6.8 (1.1–43.5) 13.6 (1.0–179.0)	0.0032 0.0283 0.0172	0.727^e
NDRG4 (promoter)	Xiao , 2015 [32]	China	CRC Cn	84 16	n-MSP	--	--	I/II III/IV	48 36	-- --	-- --	0.209^f
NDRG4 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	15.6 (2.0–123.4)	0.001	I/II III/IV	32 24	10.9 (1.3–94.2) 23.4 (2.7–200.9)	0.0098 0.0002	0.200
OSMR (promoter)	Kim, 2009 [24]	Belgium	CRC Cn	69 81	qMSP	11.6 (3.8–35.6)	< 0.001	I II III IV	18 27 18 6	2.4 (0.4–14.3) 24.1 (6.8–84.8) 15.4 (3.9–60.6) 3.9 (0.4–41.2)	0.323 < 0.001 < 0.001 0.236	0.010^e
RASSF2: Region 1 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	0.5 (0.0–10.7)^c 8.3 (1.9–37.5) 3.6 (0.8–15.6) 13.8 (4.0–47.9)	0.678 0.001 0.072 < 0.001	I/II III/IV	40 44	12.2 (3.2–47.2) 15.4 (4.1–57.4)	< 0.001 < 0.001	0.641^f
RASSF2: Region 2 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	1.3 (0.1–13.1) 2.9 (0.5–18.5) 2.1 (0.4–10.6) 20.4 (6.0–69.7)	0.818 0.234 0.373 < 0.001	I/II III/IV	40 44	10.7 (2.7–41.7) 33.5 (9.2–121.7)	< 0.001 < 0.001	0.015^f
SDC2	Niu, 2017 [51]	China	AA CRC Cn	122 196 179	qMSP	19.4 (9.7–38.5) 59.8 (30.1–118.8)	< 0.001 < 0.001	I/II III/IV	87 109	72.6 (32.0–164.5) 52.0 (24.7–109.6)	< 0.001 < 0.001	0.92 0.373^f
SDC2	Han, 2019 [28]	South Korea	NAA 0/ AA Ad CRC Cn	41 6 47 242 245	LTE-qMSP	3.0 (1.3–6.8) 46.0 (5.2–410.6) 4.3 (2.1–9.1) 83.6 (46.1–151.8)	0.008 < 0.001 < 0.001 < 0.001	I II III IV	55 70 96 21	54.1 (22.9–127.8) 98.2 (38.5–250.7) 79.2 (36.4–172.5) 388.8 (22.8–6619.3)^c	< 0.001 < 0.001 < 0.001 < 0.001	0.302^e
SDC2	Oh, 2017 [35]	South Korea	NAA CRC Cn	21 50 22	LTE-qMSP	5.0 (0.9–27.7) 90.0 (16.1–503.8)	0.054 < 0.001	I II III IV	12 17 10 11	50.0 (6.1–409.1) 75.0 (9.5–595.1) 90.0 (7.2–1125.5) 188.6 (8.3–4275.8)^c	< 0.001 < 0.001 < 0.001 < 0.001	0.710^e
SFRP2 (promoter)	Kriegshäuser, 2017 [38]	Austria	CRC Cn	2 22	MSRH Methylt	10.0 (2.1–46.6)	0.002	I II	16 18	27.9 (1.1–713.2)^c 8.1 (1.7–39.1)	0.01 0.006	0.497^e
SFRP2 (promoter)	Zhang, 2014 [50]	China	NAA AA Ad CRC Cn	20 15 35 48 30	MSP	41.5 (2.2–774.6)^c 89.2 (4.6–1733.0)^c 64.5 (3.7–1137.2)^c 78.0 (4.5–1350.0)^c	0.000 < 0.001 < 0.001 < 0.001	I/A II/B III/C IV/D	7 20 14 7	134.2 (5.6–3192.6)^c 61.0 (3.3–1133.8)^c 79.8 (4.1–1563.0)^c 78.4 (3.5- 1783.6)^c	< 0.001 < 0.001 < 0.001 < 0.001	0.812^e
SFRP2 (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	12.0 (3.8–38.3)	< 0.001	I/II III/IV	32 24	9.0 (2.6–31.2) 18.0 (4.7–68.5)	0.0002 < 0.001	0.212
SFRP2 (promoter)	Tang, 2011 [47]	China	AA CRC Cn	63 169 30	MSP	11.9 (2.6–54.5) 73.6 (16.6–327.5)	0.000 < 0.001	I/II III/IV	99 70	67.5 (14.7–310.8) 84.0 (17.3–409.1)	< 0.001 < 0.001	0.614^f
SFRP2: Region 1 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	4.4 (1.0–18.6) 11.5 (3.1–41.9) 7.4 (2.3–24.3) 36.3 (12.3–107.8)	0.033 < 0.001 0.000 < 0.001	I/II III/IV	40 44	36.9 (11.4–119.8) 35.9 (11.2–114.7)	< 0.001 < 0.001	0.950^f
SFRP2: Region 2 (promoter)	Nagasaka, 2009 [45]	Japan	NAA AA Ad CRC Cn	29 27 56 84 113	Hi-SA (n-MSP)	3.5 (0.9–13.8) 6.2 (1.7–22.1) 4.7 (1.5–14.5) 13.3 (4.9–36.1)	0.066 0.002 0.004 < 0.001	I/II III/IV	40 44	13.0 (4.3–39.0) 13.6 (4.6–40.2)	< 0.001 < 0.001	0.915^f
SFRP2 (promoter)	Wang, 2008 [43]	China	AA CRC Cn	34 69 30	qMSP (Methy-Light)	22.6 (4.6–111.2) 93.3 (18.9–460.7)	< 0.001 < 0.001	I/II III/IV	30 39	70.0 (12.5–393.4) 122.5 (20.9–718.2)	< 0.001 < 0.001	0.433 0.488^e
SNCA (promoter)	Yang, 2017 [52]	China	Ad CRC Cn	49 31 64	qMSP	9.2 (3.8–22.6)^g 11.3 (3.7–34.8)^g	< 0.001 < 0.001	I/II III/IV	17 13	14.0 (3.6–55.1) 16.5 (3.3–82.5)	< 0.001 < 0.001	1.000^e
SNCA (promoter)	Li, 2015 [27]	China	CRC Cn	89 30	MSP	138.6 (8.2–2349.8)^{c, h}	< 0.001	I/A II/B III/C	17 36 36	107.9 (5.6–2073.1)^{c, h} 239.9 (13.1–4391.9)^{c, h} 119.6 (6.7–2122.1)^{c, h}	< 0.001 < 0.001 < 0.001	0.323
SPART (promoter)	Zhang, 2013 [48]	China	CRC Cn	96 30	MSP	242.4 (14.2–4142.3)^c	< 0.001	I	21	117.9 (6.3–2209.1)^c	< 0.001	0.307
TLX2 (promoter/exon 1)	Liu, 2019 [40]	China	AA CRC Cn	77 80 83	qMSP	32.0 (9.3–110.2) 210.4 (54.8–807.6)	< 0.001 < 0.001	I/II III/IV	43 37	116.7 (29.2–466.1) 137.8 (32.4–585.4)	< 0.001 < 0.001	0.059
VIM (promoter)	Lu, 2014 [49]	China	CRC Cn	56 40	MSP	4.0 (1.4–10.9)	0.006	I/II III/IV	32 24	3.9 (1.3–11.9) 4.1 (1.2–13.3)	0.015 0.018	0.938
VIM (promoter)	Itzkowitz, 2008 [39]	USA	CRC Cn	42 241	MSP	19.6 (8.5–45.2)	< 0.001	I II III IV	11 14 14 3	46.1 (5.7–369.3) 27.6 (6.0–128.0) 8.3 (2.7–26.0) 31.9 (1.6–629.7)^c	< 0.001 < 0.001 < 0.001 0.001	0.333^e
VIM (exon 1)	Chen, 2005 [41]	USA	CRC Cn	94 198	MSP	7.5 (4.1–13.9)	< 0.001	I/II III/IV	60 34	6.8 (3.4–13.6) 8.9 (3.9–20.1)	< 0.001 < 0.001	0.533^f
WIF-1 (promoter)	Zhang, 2014 [50]	China	NAA AA Ad CRC Cn	20 15 35 48 30	MSP	15.6 (1.7–140.2) 33.1 (3.5–310.3) 24.4 (3.0–199.7) 44.3 (5.6–352.8)	0.003 < 0.001 0.000 < 0.001	I/A II/B III/C IV/D	7 20 14 7	38.7 (3.2–467.8) 67.7 (7.4–617.5) 29.0 (3.1–275.7) 38.7 (3.2–467.8)	0.000 < 0.001 0.000 0.000	0.661^e

Notes: Stages I/II/III/IV as per Union for International Cancer Control (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 real-time 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
^aStatistical significance for OR
^bStatistical significance for association between methylation level and CRC stage
^cCalculated using Haldane–Anscombe correction (0.5 added to each cell) [53, 54]
^dAs reported in the article
^eCalculated using Fisher’s exact test
^fCalculated using chi-square test
^gModel adjusted for age and sex
^hSum of methylation + stool samples divided by stages is not equal to the total number of methylation + CRC stool samples

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