The clinical value of mismatch repair protein combined with serum tumor markers and Ki-67 proliferation index in the prognostic evaluation of colorectal cancer

doi:10.19401/j.cnki.1007-3639.2022.03.007

Abstract

Abstract:

Background and purpose: Colorectal cancer is one of the most common malignant tumors of digestive system. The incidence of colorectal cancer has increased significantly in China in recent years. Various clinical and pathological indicators are helpful for the diagnosis, clinical staging and prognostic evaluation of colorectal cancer. This study aimed to observe the correlation between the expression of mismatch repair protein and serum tumor markers and Ki-67 proliferation index in colorectal cancer, and to analyze the prognostic value of mismatch repair protein, serum tumor markers and Ki-67 proliferation index. Methods: Data of 234 patients with colorectal cancer were collected after surgery in Huadong Hospital Affiliated to Fudan University from July 2014 to June 2018, and the preoperative serum levels of tumor markers (CEA, CA19-9, CA72-4, CA12-5), Ki-67 proliferation index and mismatch repair protein expression rate in surgical specimens were analyzed, in order to find the relationship between these clinicopathological features and prognosis of colorectal cancer. Results: Among 234 postoperative specimens of colorectal cancer patients, a total of 29 cases (12.4%) had defective expression of mismatch repair protein (dMMR), and 205 cases (87.6%) had normal expression of mismatch repair protein (pMMR). In the correlation analysis of clinicopathological features, there were statistically significant differences in tumor primary site, differentiation type, stage, T stage and lymph node metastasis between dMMR group and pMMR group (P<0.05). In the correlation analysis of the observed indicators, the differences in Ki-67 proliferation index, preoperative CEA and CA72-4 levels between dMMR group and pMMR group were statistically significant (P<0.05). Among the univariate prognostic analyses, the overall survival rate was significantly lower in the lymph node metastasis group and the advanced stage group (P<0.001). There was significant difference in overall survival rate between dMMR group (100%) and pMMR group (83%) (P<0.05). In the prognostic analysis of the preoperative tumor markers, CEA and CA72-4 levels had prognostic value in survival analysis (P<0.05). Multivariate COX regression analysis of 5 variables showed no significant correlation between expression of mismatch repair protein and lymph node metastasis in prognostic analysis, while significant correlation between staging and preoperative CA72-4 level was found in prognostic analysis (P<0.05). It was suggested that staging and preoperative CA72-4 level were the most important risk factors affecting the prognosis of colorectal cancer patients. Conclusion: dMMR was more common in right-sided colon cancer and in poorly differentiated adenocarcinoma and mucinous adenocarcinoma with poor type. T stage was late, while general pathological stage was early. Lymph node metastasis was rare. In dMMR group, Ki-67 proliferation index was mostly below the mean level (<70% expression), most patients had normal preoperative CEA level and elevated preoperative CA72-4 level. The dMMR group had a higher survival rate compared with the pMMR group, and later stage and increased preoperative CA72-4 level were risk factors affecting prognosis of patients. The expression deficiency of mismatch repair protein has certain prognostic value in patients with colorectal cancer.

Key words: Mismatch repair protein, Serum tumor marker, Ki-67 proliferation index, Colorectal cancer, Prognosis

CLC Number:

R735.3

CHEN Xi, ZENG Xiaoying, CHEN Jiayan, LIU Fei, TANG Xi. The clinical value of mismatch repair protein combined with serum tumor markers and Ki-67 proliferation index in the prognostic evaluation of colorectal cancer[J]. China Oncology, 2022, 32(3): 243-250.

Figures/Tables 4

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References 20

[1]	SIEGEL R L, MILLER K D, FUCHS H E, et al. Cancer Statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33. doi: 10.3322/caac.v71.1
[2]	吴春晓, 顾凯, 龚杨明, 等. 2015年中国结直肠癌发病和死亡情况分析[J]. 中国癌症杂志, 2020, 30(4): 241-245.
	WU C X, GU K, GONG Y M, et al. Analysis of incidence and mortality of colorectal cancer in China, 2015[J]. China Oncol, 2020, 30(4): 241-245.
[3]	姚宏伟, 吴鸿伟, 刘荫华. 美国癌症联合委员会第8版结直肠癌分期更新及其“预后和预测”评价体系[J]. 中华胃肠外科杂志, 2017, 20(1): 24-27.
	YAO H W, WU H W, LIU Y H. Improvement of prognostic and predictive network of colorectal cancer based upon the 8th edition of AJCC colorectal cancer staging system[J]. Chin J Gastrointest Surg, 2017, 20(1): 24-27.
[4]	吴敏, 龙静, 杨瑶. 血清肿瘤标志物联合检验应用于结直肠癌临床诊断的价值分析[J]. 国际检验医学杂志, 2017, 38(17): 2484-2486.
	WU M, LONG J, YANG Y. Value of combined test of serum tumor markers in clinical diagnosis of colorectal cancer[J]. Int J Lab Med, 2017, 38(17): 2484-2486.
[5]	李勇, 姜世平, 高霞. Ki-67和CK20及CEA的表达与结直肠癌临床病理特征的关系及意义[J]. 中国现代普通外科进展, 2017, 20(5): 394-396.
	LI Y, JIANG S P, GAO X. Relationship and significance between the expression of Ki-67, CK20 and CEA and clinicopathological features of colorectal cancer[J]. Chin J Curr Adv Gen Surg, 2017, 20(5): 394-396.
[6]	RUBENSTEIN J H, ENNS R, HEIDELBAUGH J, et al. American gastroenterological association institute guideline on the diagnosis and management of lynch syndrome[J]. Gastroenterology, 2015, 149(3): 777-782; quize16-7.
[7]	BENSON A B, VENOOK A P, AL-HAWARY M M, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2021. 19(3): 329-359. doi: 10.6004/jnccn.2021.0012
[8]	中华人民共和国国家卫生健康委员会. 中国结直肠癌诊疗规范(2020年版)[J]. 中华外科杂志, 2020, 58(8): 561-585.
	National Health Commission of the People's Republic of China. Chinese protocol of diagnosis and treatment of colorectal cancer (2020 edition)[J]. Chin J Surg, 2020, 58(8): 561-585.
[9]	韩安家, 黄艳, 来茂德. 肿瘤病理诊断规范(结直肠癌)[J]. 中华病理学杂志, 2016, 45(12): 822-824.
	HAN A J, HUANG Y, LAI M D. Diagnostic criteria of tumor pathology (colorectal cancer)[J]. Chin J Pathol, 2016, 45(12): 822-824.
[10]	于显博, 王海江, 孙振强, 等. 散发性结直肠癌患者错配修复基因蛋白表达水平及其临床意义[J]. 中国全科医学, 2014, 17(8): 883-887.
	YU X B, WANG H J, SUN Z Q, et al. Mismatch repair gene protein expression and clinical significance in patients with sporadic colorectal carcinoma[J]. Chin Gen Pract, 2014, 17(8): 883-887.
[11]	JUNG S B, LEE H I, OH H K, et al. Clinico-pathologic parameters for prediction of microsatellite instability in colorectal cancer[J]. Cancer Res Treat, 2012, 44(3): 179-186. doi: 10.4143/crt.2012.44.3.179
[12]	KIM C G, AHN J B, JUNG M, et al. Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers[J]. Br J Cancer, 2016, 115(1): 25-33. doi: 10.1038/bjc.2016.161
[13]	NICOLINI A, FERRARI P, DUFFY M J, et al. Intensive risk-adjusted follow-up with the CEA, TPA, CA19.9, and CA72.4 tumor marker panel and abdominal ultrasonography to diagnose operable colorectal cancer recurrences: effect on survival[J]. Arch Surg, 2010, 145(12): 1177-1183. doi: 10.1001/archsurg.2010.251
[14]	陈舒颖, 邱芳华, 李秋明, 等. 血清DCD、CA199、CA724和CEA联合检测对大肠癌的诊断价值[J]. 实用医学杂志, 2017, 33(15): 2482-2485.
	CHEN S Y, QIU F H, LI Q M, et al. Value of combined detection of serum DCD, CA199, CA724, and CEA in diagnosis of colorectal cancer[J]. J Pract Med, 2017, 33(15): 2482-2485.
[15]	陈蕾, 姜北海, 邸佳柏, 等. 术前检测癌胚抗原和糖链抗原199对结直肠癌Ⅱ~Ⅲ期患者预后的判断价值[J]. 中华胃肠外科杂志, 2015(9): 914-919.
	JIANG B H, DI J B, ZHANG C H, et al. Predictive value of preoperative detection of CEA and CA199 for prognosis in patients with stage Ⅱ-Ⅲ colorectal cancer[J]. Chin J Gastrointest Surg, 2015(9): 914-919.
[16]	邹超世, 林英, 刘康海, 等. 多种肿瘤标志物联合检测诊断结直肠癌的临床价值及预后监测研究[J]. 国际检验医学杂志, 2018, 39(23): 2960-2963.
	ZOU C S, LIN Y, LIU K H, et al. Clinical value and prognostic monitoring of combined detection of multiple tumor markers in the diagnosis of colorectal cancer[J]. Int J Lab Med, 2018, 39(23): 2960-2963.
[17]	KOGANEMARU S, INOSHITA N, MIURA Y, et al. Prognostic value of programmed death-ligand 1 expression in patients with stage Ⅲ colorectal cancer[J]. Cancer Sci, 2017, 108(5): 853-858. doi: 10.1111/cas.13229
[18]	傅桂霞. Array-ELISA检测6项肿瘤标志物诊断结直肠癌的临床价值分析[J]. 川北医学院学报, 2017, 32(5): 781-784.
	FU G X. Clinical value of Array-ELISA in detecting six tumor markers in diagnosis of colorectal cancer[J]. J North Sichuan Med Coll, 2017, 32(5): 781-784.
[19]	史汉蒙, 司君利, 崔伟丽, 等. 肿瘤相关巨噬细胞计数、基质金属蛋白酶-2及Ki-67的表达与结直肠癌预后的关系[J]. 中华消化杂志, 2015(6): 405-407.
	SHI H M, SI J L, CUI W L, et al. Relationship between tumor associated macrophage count, matrix metalloproteinase-2 and Ki-67 expression and prognosis of colorectal cancer[J]. Chin J Dig, 2015(6): 405-407.
[20]	MELLING N, KOWITZ C M, SIMON R, et al. High Ki-67 expression is an independent good prognostic marker in colorectal cancer[J]. J Clin Pathol, 2016, 69(3): 209-214. doi: 10.1136/jclinpath-2015-202985

Subgroup	dMMR	pMMR	χ² value	P value	Subgroup	dMMR	pMMR	χ² value	P value
Gender			0.205	0.651	Positive	8	104
Male	17	111			Negative	21	101
Female	12	94			Vascular invasion			0.733	0.392
Age/year			0.098	0.755	Positive	7	36
≤65	11	84			Negative	22	169
>65	18	121			Nerve invasion			0.597	0.440
Tumor primary site			18.346	<0.001	Positive	1	15
Right side	20	59			Negative	28	190
Left side	9	146			Ki-67			10.818	0.001
Differentiation type			38.050	<0.001	Low positive rate	15	47
High and middle adenocarcinoma	9	170			High positive rate	14	158
Poorly, mucinous adenocarcinoma	20	35			Preoperative CEA			5.309	0.021
Stage			14.656	0.002	Normal	22	109
Ⅰ	1	32			High	7	96
Ⅱ	20	68			Preoperative C19-9			2.646	0.104
Ⅲ	8	97			Normal	19	162
Ⅳ	0	8			High	10	43
T stage			9.414	0.024	Preoperative CA72-4			12.340	<0.001
T₁	1	13			Normal	17	175
T₂	0	28			High	12	30
T₃	22	149			Preoperative CA12-5			0.083	0.774
T₄	6	15			Normal	26	180
Lymph node metastasis			5.454	0.020	High	3	25

Prognostic factor	Total	Deaths	Survival n(%)	χ² value	P value
Gender				0.471	0.492
Male	127	17	110 (86.6)
Female	102	17	85 (83.3)
Age/year				3.523	0.061
≤65	92	9	83 (90.2)
>65	137	25	112 (81.8)
Tumor primary site				2.127	0.145
Right side	78	8	70 (89.7)
Left side	151	26	125 (82.8)
Differentiation type				1.474	0.225
High and middle adenocarcinoma	174	23	151 (86.8)
Poorly, mucinous adenocarcinoma	55	11	44 (80.0)
Stage				286.080	<0.001
Ⅰ	33	0	33 (100.0)
Ⅱ	88	1	87 (98.9)
Ⅲ	100	25	75 (75.0)
Ⅳ	8	8	0 (0.0)
T stage				6.481	0.090
T₁	14	0	14 (100.0)
T₂	28	1	27 (96.4)
T₃	167	29	138 (82.6)
T₄	20	4	16 (80.0)
Lymph node metastasis				37.510	<0.001
Positive	122	2	120 (98.4)
Negative	107	32	75 (70.1)
Vascular invasion				0.716	0.398
Positive	43	8	35 (81.4)
Negative	186	26	160 (86.0)
Nerve invasion				2.606	0.106
Positive	16	0	16 (100.0)
Negative	213	34	179 (84.0)
MMR				6.063	0.014
dMMR	29	0	29 (100.0)
pMMR	200	34	166 (83.0)
Ki-67				2.598	0.107
Low positive rate	59	5	54 (91.5)
High positive rate	170	29	141 (82.9)
Preoperative CEA				10.320	0.001
Normal	130	11	119 (91.5)
High	99	23	76 (76.8)
Preoperative C19-9				2.731	0.098
Normal	179	23	156 (87.2)
High	50	11	39 (78.0)
Preoperative CA72-4				9.804	0.002
Normal	190	22	168 (88.4)
High	39	12	27 (69.2)
Preoperative CA12-5				2.103	0.147
Normal	204	28	176 (86.3)
High	25	6	19 (76.0)

Variable	survival time
Variable	B	SE	Wald χ²	P value	Exp (B)	HR (95.0% CI)
Preoperative CA72-4	0.850	0.407	4.374	0.036	2.341	1.055-5.193
Preoperative CEA	0.047	0.416	0.013	0.910	1.048	0.464-2.369
Stage	3.556	0.487	53.314	0.000	35.036	13.487-91.014
Lymph node metastasis	-0.785	0.828	0.898	0.343	0.456	0.090-2.312
MMR	13.344	358.219	0.001	0.970	623 983.018	0.000