Deficient DNA mismatch repair is associated with favorable prognosis in Thai patients with sporadic colorectal cancer

Table 1 Clinical characteristics of 211 patients with sporadic colorectal cancer n (%)

Variables	Value
No. of patients	211 (100)
Median age (yr, range)	63 (33-95)
Age (yr)
≤ 50	30 (14.2)
> 50	181 (85.8)
Sex
Female	105 (49.8)
Male	106 (50.2)
Site
Right-sided	43 (20.8)
Left-sided	73 (34.6)
Rectum	91 (43.1)
Synchronous lesions	4 (1.9)
Stage
I	32 (15.2)
II	65 (30.8)
III	85 (40.3)
IV	29 (13.7)
Bowel wall invasion
pT1	4 (1.9)
pT2	44 (20.8)
pT3	146 (69.2)
pT4	17 (8.1)
Lymph node metastasis
pN0	105 (49.8)
pN1	60 (28.4)
pN2	46 (21.8)
Distant metastasis
No	182 (86.3)
Yes	29 (13.7)
Invasion
NO	118 (55.9)
LVI	47 (22.3)
PNI	15 (7.1)
Both LVI/PNI	31 (14.7)
Differentiation
Well	32 (15.2)
Moderately	171 (81)
Poorly	8 (3.8)

pT: Pathological tumor stage; pN: Pathological nodal stage; ALI: Angiolymphatic invasion; PNI: Perineural invasion.

Table 2 Interpretation of immunohistochemistry for mismatch repair status

MMR mutation	IHC staining
	MLH-1	MSH-2	MSH-6	PMS-2
MLH-1	-	+	+	-
MSH-2	+	-	-	+
MSH-6	+	+	-	+
PMS-2	+	+	+	-

MMR: Mismatch repair; IHC: Immunohistochemistry.

Table 3 Prevalence of mismatch repair and BRAF status n (%)

Variables	All cases
MMR status	n = 211
IHC method	164 (77.73)
pMMR	154
dMMR	10
MLH-1	4
MSH-2	6
MSH-6	0
PMS-2	0
MSI method	44 (20.85)
MSI-H	21
MSI-L/MSI-S	23
Unknown	3 (1.42)
BRAF status
Wild type	188 (89.1)
Mutation	23 (10.9)

pMMR: Proficient mismatch repair; dMMR: Deficient mismatch repair; MSI-H: High-level MSI; MSI-L: Low-level MSI; MSS: Microsatellite stable.

Table 4 Association between mismatch repair/BRAF status and clinicopathological factors

	MMR status(n = 208)			BRAF status(n = 211)
Variable	pMMR	dMMR	P value	Wild type	Mutant	P value
Gender
Female	87	16	0.800	94	11	0.844
Male	90	15		94	12
Age (yr)
≤ 50	24	6	0.397	29	1	0.151
> 50	153	25		159	22
Site
Right-sided	31	11	0.037a	36	7	0.510
Left-sided	59	12		67	6
Rectum	84	7		81	10
Synchronous lesions	3	1		4	0
Stage
I	25	7	0.053	30	2	0.552
II	55	8		58	7
III	68	16		73	12
IV	29	0		27	2
Invasion
No	99	17	0.910	106	12	0.701
LVI or PNI or both	78	14		82	11
Differentiation
Well-moderately	172	28	0.067	180	23	0.313
Poorly	5	3		8	0
Bowel wall invasion
pT1	3	1	0.511	4	0	0.410
pT2	34	9		39	5
pT3	126	18		128	18
pT4	14	3		17	0
Lymph node metastasis
pN-	88	15	0.891	96	9	0.280
pN+	89	16		92	14
Distant metastasis
No	148	31	0.015a	161	21	0.456
Yes	29	0		21	2

^aP < 0.05 vs control. MMR: Mismatch repair; pT: Pathological tumor stage; pN: Pathological nodal stage; ALI: Angiolymphatic invasion; PNI: Perineural invasion.

Table 5 Association between mismatch repair status and BRAF V600E

	MMR status
BRAF	dMMR	pMMR	P value
Normal	25	160	0.11
V600E	6	17

MMR: Mismatch repair; dMMR: Deficient mismatch repair; pMMR: Proficient mismatch repair.

Table 6 Univariate analysis of prognostic factors influencing disease-free survival and overall survival

Variable	n	DFS		OS
		Median survival (mo)	P value	Median survival (mo)	P value
Gender
Female	105	NR		NR
Male	106	NR	0.528	NR	0.640
Age (yr)
≤ 50	30	NR		NR
> 50	181	NR	0.695	NR	0.424
Site
Right-sided	43	NR		NR
Left-sided	73	NR		NR
Rectum	91	NR		NR
Synchronous lesions	4	NR	0.682	NR	0.788
Stage
I	32	NR		NR
II	65	NR	< 0.0001a	NR	< 0.0001a
III	85	66.7	< 0.0001a	NR	< 0.0001a
IV	29	10.4	< 0.0001a	21.6	< 0.0001a
Invasion
No invasion	118	NR		NR
LVI or PNI or both	93	52.8	0.002a	57.13	< 0.0001a
Differentiation
Well-moderately	203	NR		NR
Poorly	8	29.83	0.575	40.67	0.306
Bowel wall invasion
pT1-T2	48	NR		NR
pT3	146	62.23	0.011a	NR	< 0.0001a
pT4	17	66.73	0.122	66.733	< 0.0001a
Lymph node metastasis
pN-	105	NR		NR
pN+	106	27.57	< 0.0001a	54	< 0.0001a
Distant metastasis
No	182	-	-	NR	< 0.0001a
Yes	29	-	-	21.6
BRAF status
Wild type	188	NR	0.794	NR	0.465
Mutation	23	NR		NR
MMR status
pMMR	177	NR	0.004a	NR	0.006a
dMMR	31	NR		NR

^aP < 0.05 vs control. DFS: Disease-free survival; OS: Overall survival; NR: Not reached; ALI: Angiolymphatic invasion; PNI: Perineural invasion; pT: Pathological tumor stage; pN: Pathological nodal stage; pMMR: Proficient mismatch repair; dMMR: Deficient MMR.

Table 7 Independent risk factors correlating with disease-free survival and overall survival of stage I-IV colorectal cancer patients by Cox’s proportional hazard regression analysis

	Adjusted analysis for DFS			Adjusted analysis for OS
Variable	HR	95%CI	P value	HR	95%CI	P value
Stage
Stage I1
Stage II	1.23	0.43-3.62	0.702	1.47	0.40-5.40	0.559
Stage III	4.03a	1.57-10.32	0.004a	4.94a	1.50-16.27	0.009a
Stage IV	-			32.64a	9.57-111.27	< 0.001a
Invasion
No invasion1
LVI/PNI/both	1.17	0.75-1.81	0.486	1.36	0.85-2.19	0.204
Differentiation
Well-moderate1
Poorly	2.57	0.87-7.43	0.083	3.78	1.27-11.21	0.017a
MMR status
pMMR1
dMMR	0.30	0.15-0.77	0.013a	0.29a	0.10-0.84	0.023a

¹Reference.

^aP < 0.05 vs control. DFS: Disease-free survival; OS: Overall survival; HR: Hazard ratio; MMR: Mismatch repair; pMMR: Proficient MMR; dMMR: Deficient MMR.