Loss of heterozygosity: An independent prognostic factor of colorectal cancer

Table 1 Frequency of LOH and MSI of tumor suppressor genes in sporadic colorectal cancers.

Marker	Informative /Total (%)	LOH/Informative (%)	MSI No./Total (%)
NM23-H1	125/207 (60.4)	43/125 (31.6)	4/164 (2.4)
APC	121/207 (58.5)	56/121 (47.8)	10/151 (6.6)1
Tp53.alu	103/207 (49.8)	67/103 (65.0)	1/140 (0.7)
HPC1	127/207 (61.4)	15/127 (11.8)	6/192 (3.1)
D8S254	89/207 (43.0)	46/89 (51.7)	5/161 (3.1)
DCC	98/207 (47.3)	63/98 (64.3)	3/144 (2.1)
hMSH2	153/207 (73.9)	24/153 (15.7)	19/183 (10.4)1
hMLH1	99/207 (47.8)	26/99 (26.3)	11/181 (6.1)
MET	91/207 (44.0)	27/91 (29.7)	7/180 (3.9)
Tp53.pcr15	80/207 (38.6)	31/80 (38.8)	5/174 (2.9)
MYCL1	110/207 (53.1)	38/110 (34.5)	5/169 (3.0)
Bat-25	30/207 (14.5)	3/30 (10)	22/204 (9.8)1
Bat-26	41/207 (19.8)	4/41 (4.4)	15/203 (7.4)1
Mfd15	33/207 (15.9)	2/33 (7.2)	9/205 (4.4)1

¹Reference markers according to the international criteria for the determination of MSI[13].

Table 2 Comparison between clinico-pathological features of loss of heterozygosity-high and loss of heterozygosity-low in colorectal cancer, n (%).

Features	Total	LOH-high	LOH-low	P
Number of cases	207	93 (44.9)	114 (55.1)
Age (yr)	66.2±12.4	67.2±12.4	65.4±12.3	0.2921
Gender (male/female)	139/68	61/32	78/36	0.7782
Location of tumor
Right colon	37 (17.9)	16 (17.2)	21 (18.4)	0.5443
Left colon	85 (41.1)	42 (45.2)	43 (37.7)
Rectum	85 (41.1)	35 (37.6)	50 (43.9)
TNM stage
I	25 (12.1)	7 (7.5)	18 (15.8)	<0.0014
II	73 (35.3)	22 (23.7)	51 (44.7)
III	68 (32.9)	37 (39.8)	31 (27.2)
IV	41 (19.8)	27 (29.0)	14 (12.3)
Invasive pattern
Expanding	52 (25.1)	20 (21.5)	32 (28.1)	0.2862
Infiltrative	155 (74.9)	73 (78.5)	82 (71.9)
Grade
Well-differentiated	5 (2.4)	2 (2.2)	3 (2.6)	0.2633
Moderate differentiated	182 (87.9)	81 (87.0)	101 (88.6)
Poorly differentiated	20 (9.7)	10 (10.8)	10 (8.8)
Lymphovascular invasion
Yes	48 (23.2)	27 (56.3)	21 (43.7)	0.1022
No	159 (76.8)	66 (41.5)	93 (58.5)
Mucin production
Yes	29 (14.0)	9 (9.7)	20 (17.5)	0.1552
No	178 (86.0)	84 (90.3)	94 (82.5)

¹Student t test,

²Fisher exact test,

³Pearson χ² test,

⁴χ² test with linear-by-linear association.

Table 3 Comparison between clinico-pathological features of MSI-H and MSS in colorectal cancer, n (%).

Features	Total	MSI-H	MSS	P
Number of cases (%)	207	15 (7.25)	192 (92.7)
Age (yr)	66.2±12.4	69.7±14.8	65.9±12.2	0.2481
Gender(male/female)	139/68	8/7	131/61	0.3692
Location of tumor
Right colon	37 (17.9)	7 (46.7)	30 (15.6)	0.0053
Left colon	85 (41.1)	2 (13.3)	83 (43.2)
Rectum	85 (41.1)	6 (40.0)	79 (41.2)
TNM stage
I	25 (14.2)	1 (6.7)	24 (12.5)	0.7804
II	73 (36.8)	6 (40.0)	67 (34.9)
III	68 (31.6)	6 (40.0)	62 (32.3)
IV	41 (17.4)	2 (13.3)	39 (20.3)
Invasive pattern
Expanding	52 (25.1)	4 (26.7)	48 (25.0)	1.02
Infiltrative	155 (74.9)	11 (73.3)	144 (75.0)
Grade of differentiation
Well	5 (2.4)	0	5 (2.6)	<0.0013
Moderate	182 (87.9)	9 (60.0)	173 (90.1)
Poor	20 (9.7)	6 (40.0)	14 (7.3)
Lymphovascular invasion
Yes	48 (23.2)	1 (6.7)	47 (24.5)	0.2092
No	159 (76.8)	14 (93.3)	145 (75.5)
Mucin component
Yes	29 (14.0)	7 (46.7)	22 (11.5)	0.0012
No	178 (86.0)	8 (53.3)	170 (88.5)

¹Student t test,

²Fisher exact test,

³Pearson χ² test,

⁴χ² test with linear-by-linear association.

Table 4 Correlation of the clinico-pathological factors with three-year disease-free survival in potentially cured colorectal cancer patients (stage I, II, III patients).

Variables	Number of cases	3-yr disease -free survival	P1
Gender
Male	116	70	0.614
Female	50	75
Preoperative CEA level
<5 ng/mL	80	82	0.003
>5 ng/mL	86	63
TNM stage
I	25	95	<0.001
II	73	84
III	68	47
Lymphovascular permeation
No	129	73	0.091
Yes	37	63
Invasive pattern of tumor
Expansive	45	73	0.517
Infiltrative	121	68
Grade of differentiation
Well	3	100	0.004
Moderate	146	75
Poor	17	48
Mucinous component
<50%	143	72	0.642
>50%	23	68
Microsatellite instability
MSI-H	13	69	0.91
MSS	153	71
LOH status
Low	100	84	<0.001
High	66	50

¹Log-rank test

Table 5 Multivariate analysis¹.

Factors	Hazard ratio	95% CI	P
LOH (High vs Low)	3.18	1.68-5.98	<0.001
TNM	3.31	1.82-6.01	<0.001
CEA level
>5 ng/mL vs <5 ng/mL	2.3	1.21-4.37	0.011
Grade of differentiation	1.12	0.45-2.77	0.791
Lymphovascular invasion	1	0.49-2.01	0.981

¹The P value results from the hypothesis that the relative risk as determined by a multivariate binary logistic regression analysis equaled 1.0.

Table 6 Informative markers that influenced three-year DFS in potentially cured colorectal cancer patients (stage I, II, III patients).

Markers	Number of cases	3-yr disease-free survival	P1
Nm23-H1
Non-LOH	68	75	0.266
LOH	28	62
APC
Non-LOH	54	75	0.881
LOH	45	72
Tp53.alu
Non-LOH	29	92	<0.001
LOH	55	51
HPC1
Non-LOH	87	75	0.743
LOH	12	70
D8S254
Non-LOH	39	75	0.03
LOH	31	52
DCC
Non-LOH	27	79	0.042
LOH	45	55
MSH2
Non-LOH	107	73	0.972
LOH	15	75
MLH1
Non-LOH	62	66	0.287
LOH	19	57
Met ONC
Non-LOH	50	72	0.35
LOH	16	64
Tp53.pcr15
Non-LOH	42	76	<0.001
LOH	20	33
MYCL1
Non-LOH	59	71	0.421
LOH	29	65

¹Log-rank test; The markers that had frequency of informative tumors lower than 30% were excluded in the survival analysis.