IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

doi:10.3748/wjg.v20.i29.10050

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World Journal of Gastroenterology

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World J Gastroenterol. Aug 7, 2014; 20(29): 10050-10061
Published online Aug 7, 2014. doi: 10.3748/wjg.v20.i29.10050

Table 1 IGF2 differentially methylated region 0 hypomethylation in serrated lesions and non-serrated adenomas n (%)

Clinicopathological feature	Total n	IGF2 DMR0 methylation (quartile)				P value
Clinicopathological feature	Total n	Q1 (≥74.5)	Q2 (62.6-74.4)	Q3 (49.6-62.5)	Q4 ( ≤49.5)	P value
All cases	536	134	130	131	141
Sex
Male	326 (61)	78 (58)	80 (62)	92 (70)	76 (54)	0.041
Female	210 (39)	56 (42)	50 (38)	39 (30)	65 (46)	0.041
Age (mean ± SD)	61.5 ± 12.2	59.9 ± 12.3	60.8 ± 12.0	63.1 ± 11.6	62.3 ± 13.0	0.150
Tumor size (mm) (mean ± SD)	14.3 ± 11.4	9.9 ± 4.0	13.4 ± 7.4	14.7 ± 11.1	19.1 ± 17.6	< 0.0001
Tumor location
Rectum	70 (13)	11 (8.5)	14 (11)	18 (14)	27 (20)	0.061
Distal colon	161 (31)	35 (27)	43 (33)	37 (29)	46 (33)
Proximal colon	296 (56)	84 (65)	72 (56)	75 (58)	65 (47)
Histological type
Hyperplastic polyp (HP)	115 (21)	33 (25)	25 (19)	23 (18)	34 (24)	< 0.0001
Sessile serrated adenoma (SSA) without cytological dysplasia	120 (22)	60 (45)	39 (30)	15 (11)	6 (4.3)
SSA with cytological dysplasia	10 (1.9)	1 (0.8)	3 (2.3)	6 (4.6)	0 (0)
Traditional serrated adenoma (TSA) without high-grade dysplasia (HGD)	91 (17)	22 (16)	21 (16)	23 (18)	25 (18)
TSA with HGD	15 (2.8)	2 (1.5)	2 (1.5)	2 (1.5)	9 (6.4)
Non-serrated adenoma (tubular or tubulovillous adenoma) without HGD	80 (15)	11 (8.2)	17 (13)	32 (24)	20 (14)
Non-serrated adenoma with HGD	105 (20)	5 (3.7)	23 (18)	30 (23)	47 (33)

Percentage indicates the proportion of patients of each histological type who met the criteria for a specific clinical or molecular feature. P values were calculated by analysis of variance for age and tumor size and by χ² or Fisher’s exact test for all other variables. The P value for significance was adjusted by Bonferroni correction to 0.010 (= 0.05/5).

Table 2 Clinical and molecular features of serrated lesions and non-serrated adenomas (tubular or tubulovillous adenoma) according to histological type n (%)

Clinical or molecular feature	Total n	Histological type						P value
		Serrated lesion				Non-serrated adenoma
		HP	SSA without cytological dysplasia	SSA with cytological dysplasia	TSA without high-grade dysplasia (HGD)	Tubular adenoma without HGD	Tubulovillous adenoma without HGD
All cases	416	115	120	10	91	77	3
Sex
Male	263 (63)	78 (68)	72 (60)	5 (50)	55 (60)	50 (65)	3 (100)	0.36
Female	153 (37)	37 (32)	48 (40)	5 (50)	36 (40)	27 (35)	0 (0)	0.36
Age (mean ± SD)	60.3 ± 11.8	57.5 ± 12.1	57.2 ± 11.6	74.1 ± 4.7	60.9 ± 12.3	66.6 ± 11.4	66.0 ± 8.9	< 0.0001
Tumor size (mm)	10.5 ± 5.4	9.3 ± 3.7	11.6 ± 5.4	12.3 ± 6.4	9.7 ± 4.7	10.9 ± 7.2	15.7 ± 13.2	0.0069
(mean ± SD)	10.5 ± 5.4	9.3 ± 3.7	11.6 ± 5.4	12.3 ± 6.4	9.7 ± 4.7	10.9 ± 7.2	15.7 ± 13.2	0.0069
Tumor location
Rectum	42 (10)	15 (13)	0 (0)	0 (0)	16 (18)	10 (14)	1 (33)	< 0.0001
Distal colon	127 (31)	44 (39)	17 (14)	1 (10)	39 (44)	25 (34)	1 (33)
Proximal colon	239 (59)	54 (48)	103 (86)	9 (90)	34 (38)	38 (52)	1 (33)
BRAF mutation
Wild-type	183 (44)	59 (51)	16 (13)	2 (20)	28 (31)	75 (97)	3 (100)	< 0.0001
Mutant	231 (55)	56 (49)	104 (87)	8 (80)	61 (69)	2 (2.6)	0 (0)	< 0.0001
KRAS mutation
Wild-type	357 (87)	92 (81)	117 (98)	10 (100)	74 (83)	62 (81)	2 (67)	< 0.0001
Mutant	55 (13)	21 (19)	3 (2.5)	0 (0)	15 (17)	15 (19)	1 (33)	< 0.0001
PIK3CA mutation
Wild-type	406 (99)	113 (99)	117 (100)	10 (100)	89 (100)	74 (99)	3 (100)	0.67
Mutant	2 (0.5)	1 (0.9)	0 (0)	0 (0)	0 (0)	1 (1.3)	0 (0)	0.67
MSI status
MSS/MSI-low	408 (98)	113 (98)	119 (99)	6 (60)	90 (99)	77 (100)	3 (100)	0.0004
MSI-high	8 (1.9)	2 (1.7)	1 (0.8)	4 (40)	1 (1.1)	0 (0)	0 (0)	0.0004
IGF2 DMR0	64.5 ± 17.2	61.9 ± 20.5	73.1 ± 12.3	69.0 ± 10.8	61.6 ± 19.6	58.9 ± 16.1	61.0 ± 7.1	< 0.0001
methylation level (mean ± SD)	64.5 ± 17.2	61.9 ± 20.5	73.1 ± 12.3	69.0 ± 10.8	61.6 ± 19.6	58.9 ± 16.1	61.0 ± 7.1	< 0.0001
LINE-1	58.7 ± 5.0	58.6 ± 3.4	58.1 ± 5.4	58.3 ± 8.4	58.8 ± 4.7	59.4 ± 6.0	60.9 ± 1.4	0.59
methylation level (mean ± SD)	58.7 ± 5.0	58.6 ± 3.4	58.1 ± 5.4	58.3 ± 8.4	58.8 ± 4.7	59.4 ± 6.0	60.9 ± 1.4	0.59

Percentage indicates the proportion of patients of each histological type who met the criteria for a specific clinical or molecular feature. P values were calculated by analysis of variance for age, tumor size, methylation levels of IGF2 DMR0 and LINE-1 and by χ² or Fisher’s exact test for all other variables. The P value for significance was adjusted by Bonferroni correction to 0.0050 (= 0.05/10). HGD: High-grade dysplasia; HP: Hyperplastic polyp; MSI: Microsatellite instability; MSS: Microsatellite stable; SSA: Sessile serrated adenoma; TSA: Traditional serrated adenoma; IGF2: Insulin-like growth factor 2.

Table 3 Clinical and molecular features of sessile serrated adenomas with cytological dysplasia, traditional serrated adenomas, non-serrated adenomas (tubular or tubulovillous adenoma), and colorectal carcinomas according to disease stage n (%)

Clinical or molecular feature	Histological type									P value
	SSA with cytological dysplasia	Colorectal adenoma				Colorectal carcinoma
	SSA with cytological dysplasia	TSA without HGD	TSA with HGD	Non-serrated adenoma without HGD	Non-serrated adenoma with HGD	Stage I	Stage II	Stage III	Stage IV
All cases	10	91	15	80	105	171	217	292	114
Sex
Male	5 (50)	55 (60)	9 (60)	53 (66)	54 (51)	107 (63)	123 (57)	168 (58)	73 (64)	0.50
Female	5 (50)	36 (40)	6 (40)	27 (34)	51 (49)	64 (37)	94 (43)	124 (42)	41 (36)	0.50
Age (mean ± SD)	74.1 ± 4.7	60.9 ± 12.3	62.7 ± 13.6	66.6 ± 11.2	66.3 ± 10.5	65.1 ± 11.0	67.4 ± 11.5	66.6 ± 12.5	63.4 ± 9.5	0.0016
Tumor size (mm)	12.3 ± 6.4	9.7 ± 4.7	12.8 ± 4.3	11.0 ± 7.4	29.3 ± 17.3	26.3 ± 15.8	53.1 ± 23.5	50.5 ± 22.7	50.9 ± 19.6	< 0.0001
(mean ± SD)	12.3 ± 6.4	9.7 ± 4.7	12.8 ± 4.3	11.0 ± 7.4	29.3 ± 17.3	26.3 ± 15.8	53.1 ± 23.5	50.5 ± 22.7	50.9 ± 19.6	< 0.0001
Tumor location
Rectum	0 (0)	16 (18)	5 (33)	11 (14)	23 (22)	65 (38)	73 (34)	135 (46)	37 (33)	< 0.0001
Distal colon	1 (10)	39 (44)	7 (47)	26 (34)	27 (26)	44 (25)	64 (29)	59 (20)	42 (37)
Proximal colon	9 (90)	34 (38)	3 (20)	39 (51)	54 (52)	62 (36)	80 (37)	98 (34)	34 (30)
BRAF mutation
Wild-type	2 (20)	28 (31)	7 (47)	78 (98)	102 (98)	161 (95)	204 (94)	282 (97)	103 (95)	< 0.0001
Mutant	8 (80)	61 (69)	8 (53)	2 (2.5)	2 (1.9)	9 (5.3)	13 (6.0)	9 (3.0)	6 (5.5)	< 0.0001
KRAS mutation
Wild-type	10 (100)	74 (83)	11 (73)	64 (80)	48 (46)	108 (64)	145 (69)	202 (70)	84 (74)	< 0.0001
Mutant	0 (0)	15 (17)	4 (27)	16 (20)	57 (54)	62 (36)	66 (31)	88 (30)	29 (26)	< 0.0001
PIK3CA mutation
Wild-type	10 (100)	89 (100)	14 (93)	77 (99)	99 (94)	161 (94)	194 (89)	249 (85)	103 (90)	< 0.0001
Mutant	0 (0)	0 (0)	1 (6.7)	1 (1.3)	6 (5.7)	10 (5.9)	23 (11)	43 (15)	11 (9.7)	< 0.0001
MSI status
MSS/MSI-low	6 (60)	90 (99)	15 (100)	80 (100)	105 (100)	163 (95)	198 (91)	276 (95)	110 (96)	< 0.0001
MSI-high	4 (40)	1 (1.1)	0 (0)	0 (0)	0 (0)	8 (4.7)	19 (8.8)	16 (5.5)	4 (3.5)	< 0.0001
IGF2 DMR0	69.0 ± 10.8	61.6 ± 19.6	50.2 ± 18.7	59.0 ± 15.8	52.0 ± 13.6	55.7 ± 15.8	53.4 ± 13.3	55.5 ± 12.9	53.1 ± 12.9	< 0.0001
methylation level (mean ± SD)	69.0 ± 10.8	61.6 ± 19.6	50.2 ± 18.7	59.0 ± 15.8	52.0 ± 13.6	55.7 ± 15.8	53.4 ± 13.3	55.5 ± 12.9	53.1 ± 12.9	< 0.0001
LINE-1	58.3 ± 8.4	58.8 ± 4.7	55.7 ± 5.4	59.5 ± 5.9	56.9 ± 5.5	55.8 ± 7.2	53.1 ± 6.2	55.1 ± 6.5	54.1 ± 7.6	< 0.0001
methylation level (mean ± SD)	58.3 ± 8.4	58.8 ± 4.7	55.7 ± 5.4	59.5 ± 5.9	56.9 ± 5.5	55.8 ± 7.2	53.1 ± 6.2	55.1 ± 6.5	54.1 ± 7.6	< 0.0001

Percentage indicates the proportion of patients of each histological type who met the criteria for a specific clinical or molecular feature. P values were calculated by analysis of variance for age, tumor size, methylation levels of IGF2 DMR0 and LINE-1 and by χ² or Fisher’s exact test for all other variables. The P value for significance was adjusted by Bonferroni correction to 0.0050 (= 0.05/10). HGD: High-grade dysplasia; HP: Hyperplastic polyp; MSI: Microsatellite instability; MSS: Microsatellite stable; SSA: Sessile serrated adenoma; TSA: Traditional serrated adenoma; IGF2: Insulin-like growth factor 2.

Table 4 Clinicopathological and molecular features of fifteen traditional serrated adenomas with high-grade dysplasia

No.	Age/sex	Location	Size (mm)	KRAS mutation	BRAF mutation	PIK3CA mutation	MGMT methylation	MLH1 methylation	MSI status	LINE-1 methylation level	IGF2 DMR0 methylation level	IGF2 expression
1	75/M	Rectum	8	c.35G>A (p.G12D)	Wild	Wild	(-)	(-)	MSS/MSI-low	58	70	Weak
2	54/F	Sigmoid colon	20	c.35G>A (p.G12D)	Wild	Wild	(+)	(-)	MSS/MSI-low	53.7	39.5	Strong
3	62/F	Transverse colon	15	c.38G>A (p.G13D)	Wild	Wild	(+)	(-)	MSS/MSI-low	53.3	72.0	No expression
4	84/M	Rectum	5	c.35G>A (p.G12D)	Wild	Wild	(-)	(-)	MSS/MSI-low	65.0	26.5	Moderate
5	85/M	Sigmoid colon	12	Wild	c.1799T>A (p.V600E)	Wild	(-)	(-)	MSS/MSI-low	58.0	45.5	Strong
6	48/M	Sigmoid colon	20	Wild	c.1799T>A (p.V600E)	Wild	(-)	(-)	MSS/MSI-low	53.7	40.5	Moderate
7	69/M	Sigmoid colon	10	Wild	c.1799T>A (p.V600E)	Wild	(-)	(-)	MSS/MSI-low	58.7	52.0	No expression
8	60/M	Descending colon	9	Wild	c.1799T>A (p.V600E)	Wild	(-)	(-)	MSS/MSI-low	59.0	41.5	Moderate
9	34/M	Sigmoid colon	18	Wild	c.1799T>A (p.V600E)	Wild	(+)	(-)	MSS/MSI-low	57.3	42.0	Strong
10	61/M	Rectum	10	Wild	c.1799T>A (p.V600E)	Wild	(-)	(-)	MSS/MSI-low	56.7	29.0	Strong
11	52/F	Ascending colon	15	Wild	c.1799T>A (p.V600E)	Wild	(+)	(+)	MSS/MSI-low	57.0	57.0	Moderate
12	70/F	Rectum	13	Wild	c.1799T>A (p.V600E)	Wild	(+)	(+)	MSS/MSI-low	63.0	84.5	Weak
13	66/F	Ascending colon	12	Wild	Wild	c.1624G>A (p.E542K)	(-)	(-)	MSS/MSI-low	49.7	28.0	Moderate
14	52/M	Sigmoid colon	12	Wild	Wild	Wild	(-)	(-)	MSS/MSI-low	48.0	44.5	Moderate
15	69/F	Rectum	13	Wild	Wild	Wild	(+)	(-)	MSS/MSI-low	44.3	80.0	Weak

HGD: High-grade dysplasia; MSI: Microsatellite instability; MSS: Microsatellite stable; TSA: Traditional serrated adenoma.

Citation: Naito T, Nosho K, Ito M, Igarashi H, Mitsuhashi K, Yoshii S, Aoki H, Nomura M, Sukawa Y, Yamamoto E, Adachi Y, Takahashi H, Hosokawa M, Fujita M, Takenouchi T, Maruyama R, Suzuki H, Baba Y, Imai K, Yamamoto H, Ogino S, Shinomura Y. IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions. World J Gastroenterol 2014; 20(29): 10050-10061
URL: https://www.wjgnet.com/1007-9327/full/v20/i29/10050.htm
DOI: https://dx.doi.org/10.3748/wjg.v20.i29.10050