DNA错配修复缺陷与结直肠黏液腺癌临床病理特征的关系

Relationship of DNA mismatch repair-deficient with clinicopathological features of colorectal mucinous adenocarcinoma

目的观察结直肠黏液腺癌(MAC)患者癌组织错配修复(MMR)状态与临床病理特征的关系,探讨MMR状态对MAC患者预后的影响。方法2016年1月—2019年12月郑州大学第一附属医院行根治性切除术或姑息性切除术的MAC患者146例,术后采用免疫组织化学法检测癌组织DNA错配修复蛋白MLH1、MSH2、MSH6、PMS2及Ki-67表达。根据癌组织MMR蛋白表达情况,将146例患者分为DNA错配修复缺陷(dMMR)组和错配修复完整(pMMR)组,比较2组术前血清癌胚抗原(CEA)、糖类抗原(CA)19-9、CA72-4、CA125水平,手术方式,肿瘤部位,肿瘤直径,肿瘤类型,临床分期及淋巴结转移、脉管侵犯、神经侵犯比率等临床病理特征。记录患者生存情况,将146例患者分为生存组和死亡组,比较2组临床病理特征及MMR状态,采用多因素Cox回归分析MAC患者术后死亡的危险因素。结果(1)146例患者dMMR发生率为25.3%(37/146),右半肠癌患者dMMR发生率[39.4%(26/66)]高于左半肠癌患者[13.8%(11/80)](χ^(2)=12.570,P<0.001)。(2)dMMR组左半肠癌(29.7%)、临床分期Ⅲ~Ⅳ期(39.1%)、淋巴结转移比率(29.7%)及术前血清CEA、CA125水平升高比率(24.3%、2.7%)低于pMMR组(63.3%、61.5%、48.6%、47.7%、15.6%)(P<0.05),男性、年龄≥65岁、肿瘤直径≥5cm,有神经侵犯、有脉管侵犯、根治性手术、溃疡型肿瘤、T分期T1-2期、Ki-67≥50%及术前血清CA19-9、CA72-4水平升高比率与pMMR组比较差异均无统计学意义(P>0.05)。(3)随访至2022年12月31日,146例患者中生存91例(62.3%),其中dMMR组生存29例(78.4%),pMMR组生存62例(56.9%),dMMR组生存率高于pMMR组(χ^(2)=8.702,P=0.003)。(4)生存组dMMR(31.9%)、年龄<65岁(76.9%)、临床分期Ⅰ~Ⅱ期(64.8%)比率均高于死亡组(14.5%、56.4%、12.7%)(P<0.05),有脉管侵犯(16.5%)及术前CA72-4(35.2%)、CA125(6.6%)水平增高比率均低于死亡组(30.9%、67.3%、21.8%)(P<0.05),男性、肿瘤直径≥5cm、左半肠癌、有淋巴结转移、根治性手术、溃疡型肿瘤、T分期T1-2期、Ki-67≥50%及术前血清CEA、CA19-9水平升高比率与死亡组比较差异均无统计学意义(P>0.05)。(5)pMMR(HR=2.897,95%CI:1.288~6.518,P=0.010)、临床分期Ⅲ~Ⅳ期(HR=5.834,95%CI:2.571~13.239,P<0.001)、术前血清CA72-4水平升高(HR=2.900,95%CI:1.599~5.262,P<0.001)是MAC患者术后死亡的危险因素。结论与pMMR的MAC患者比较,dMMR的MAC患者肿瘤多位于右半结肠、临床分期较早、淋巴结转移少见;pMMR、临床分期Ⅲ~Ⅳ期、术前血清CA72-4水平升高的MAC患者死亡风险增大。

Objective To analyze the relationship between mismatch repair(MMR)status of cancer tissues and clinicopathological features in patients with colorectal mucinous adenocarcinoma(MAC),and to investigate the impact of MMR status on the prognosis.Methods From January 2016 to December 2019,146 patients with MAC were performed radical resection or palliative resection of MAC in the First Affiliated Hospital of Zhengzhou University,and underwent immunohistochemistry to detect the expressions of DNA MMR proteins MLH1,MSH2,MSH6 and PMS2 as well as Ki-67 in cancer tissues after surgery.According to the expression of MMR protein of cancer tissues,146 patients were divided into MMR-deficient(dMMR)group and MMR-proficient(pMMR)group,and the preoperative serum levels of carcinoembryonic antigen(CEA),carbohydrate antigen(CA)19-9,CA72-4 and CA125,surgical method.tumor location,tumor diameter,tumor type,clinical stage,lymph node metastasis,vascular invasion,nerve invasion and other clinicopathological features were compared between two groups.The patients were followed up till December 31,2022 to record the survival,by which 146 patients were divided into survival group and death group,and the clinical characteristics and MMR status were compared between two groups.Multivariate Cox regression was used to analyze the risk factors of mortality of MAC patients after surgery.Results(1)The incidence of dMMR in 146 patients was 25.3%(37/146).The incidence of dMMR was higher in patients with right colon cancer[39.4%(26/66)]than that in patients with left colon cancer[13.8%(11/80)](χ^(2)=12.570.P<0.001).(2)The percentages of left colon cancer,clinical stageⅢtoⅣ,lymph node metastasis,preoperative CEA increase,and preoperative CA125 increase were lower in dMMR group(29.7%,39.1%,29.7%,24.3%,2.7%)than those in pMMR group(63.3%,61.5%,48.6%,47.7%,15.6%)(_P<0.05),and there were no significant differences in the percentages of male patients,and patients with age≥65 years,tumor diameter≥5 cm,nerve invasion,vascular invasion,radical resection,ulcerative tumor,T_(1-2)stage,Ki-67≥50%,preoperative CA19-9 increase,and preoperative CA72-4 increase between two groups(P>0.05).(3)The follow-up till December 31,2022 showed that 91 patients survived(62.3%)including 29(78.4%)in dMMR group and 62(56.9%)in pMMR group.The survival rate was higher in dMMR group than that in pMMR group(χ^(2)=8.702,P=0.003).(4)The percentages of dMMR,age≥65 years old,and clinical stageⅠ-Ⅱwere higher in survival group(31.9%,76.9%,64.8%)than those in death group(14.5%,56.4%,12.7%)(P<0.05),the percentages of patients with vascular invasion and preoperative CA72-4 increase and CA125 were lower in survival group(16.5%,35.2%,6.6%)than those in death group(30.9%,67.3%,21.8%)(P<0.05),and there were no significant differences in the percentages of male patients and patients with tumor diameter≥5 cm,left colon cancer,lymph node metastasis,radical resection,ulcerative tumor,T stage,Ki-67≥50%,preoperative CEA increase and preoperative CA19-9 increase between two groups(P>0.05).(5)pMMR(HR=2.897,95%CI:1.288-6.518,P=0.010),clinical stageⅢ-Ⅳ(HR=5.834,95%CI:2.571-13.239,P<0.001),and preoperative CA72-4 increase(HR=2.900,95%CI:1.599-5.262,P<0.001)were the risk factors of mortality of MAC patients.Conclusion Patients with dMMR MAC have higher incidence of right colon cancer,earlier clinical stage,and lower metastasis rate of lymph nodes than patients with pMMR MAC,and those with pMMR,clinical stageⅢ-Ⅳand increased preoperative CA72-4 level are at a high risk of mortality.