The Effect Of Mismatch Repair Protein Expression On Regional Lymph Node Status Of Colorectal Cancer And Analysis Of Related High-risk Factors

Part Ⅰ:The relationship between the mismatch repair protein expression and regional lymph nodes status in colorectal cancerBackgroundAccording to the mechanism of tumorigenesis,colorectal cancer(CRC)could be divided into two distinct subgroups:mismatch repair proficiency(pMMR)and mismatch repair deficiency(dMMR).Compared with pMMR,CRC patients with dMMR has been found associated with DNA microsatellite instability and specific clinicopathologic features,such as younger age,more poorly differentiation and better survival,but the relationship between the expression of mismatch repair proteins and regional lymph nodes(RLNs)status remains unclear.We aim to further explore the relationship between the expression of mismatch repair proteins and RLNs status in a large CRC database,to learn more about the difference between CRC patients with dMMR and pMMR and facilitate evaluation of the scope of surgery.MethodsWe retrospectively collected clinicopathological information of CRC patients who underwent radical surgery in Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College from January 2012 to December 2015.Eligible patients were selected according to the inclusion and exclusion criteria.Immunohistochemistry(IHC)staining was used to evaluate the expression of mismatch repair proteins.Univariate and multivariate logistic regression analysis were performed and propensity score matching(PSM)was also used to decrease bias between dMMR and pMMR groups.The RLNs status,including the number of PLN/NLN,lymph node ratio,the distribution of lymphatic metastasis and so on,was analyzed.ResultsTotally,clinicopathologic data of 2940 CRC patients was collected and 2670 stage Ⅰ-ⅢCRC patients were included in this study(272 dMMR and 2398 pMMR patients)for further statistical analysis.Through PSM,baseline characteristics of the two groups were well matched.After PSM,dMMR patients had more total number of lymph node(TLN,median:28.00 vs 23.00,p<0.001),number of negative lymph node(NLN,median:27.00 vs 22.00,p<0.001),less number of positive lymph node(PLN,median:0.00(IQR,0.00-0.00)vs 0.00(IQR,0.00-3.00),p<0.001)。Furthermore,CRC patients with dMMR had significantly lower LNR(median:0.00(IQR,0.00-0.00)vs 0.00(IQR,0.00-0,12),p<0.001),log odds of positive lymph nodes(LODDS,median:-3.85 vs-3.30,p<0.001)and smaller extent of lymphatic metastases(pericolic/perirectal lymph node:21.9%vs 38.4%,p<0.001;mesenteric lymph node:10.1%vs 29.1%,p<0.001)compared with pMMR patients.In multivariate analysis,dMMR was still significantly associated with RLNs metastasis(OR:0.36,95%CI:0.23-0.55,p<0.001)and metastatic extent.ConclusionsCRC patients with dMMR are likely to have more TLN,NLN and less PLN,LNR,LODDS and smaller extent of RLNs metastases than pMMR.The expression of mismatch repair protein could be a potential molecular marker to guide the lymphadenectomy in CRC.Part Ⅱ:The risk factors for regional lymph node metastasis in mismatch repair deficient colorectal cancerBackgroundRegional lymph nodes(RLNs)are the most common sites of cancer metastases in CRC,and RLNs status is regarded as important prognostic factor.Evaluate the extent of metastasis of RLNs preoperatively could help to make individual surgery and treatment regimen,reduce complication and avoid overtreatment.However,it is still debatable about the suitable scope of lymphadenectomy in CRC,and many patients without RLNs metastasis received unnecessary lymphadenectomy.Thus,evaluate the metastasis of RLNs more accurately before surgery is needed.Compared with pMMR,CRC patients with dMMR have distinct clinicopathologic characters,such as less number and smaller extent of lymph node metastasis,however,few researches have explored the risk factors of RLNs metastasis in dMMR patients.And we aim to futher evaluate the risk factors of lymph node metastasis in dMMR patients which could help clinicians to make treatment regimen and surgery strategy.MethodsThe clinical-pathological data of colorectal cancer patients diagnosed in Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively collected from January 2012 to December 2016.Immunohistochemistry was used to determine the expression of mismatch repair proteins.Eligible patients were selected according to the inclusion and exclusion criteria,and finally 357 dMMR CRC patients who underwent radical resection was analyzed.Univariate and multivariate logistic regression analysis were performed to further analysis the relationship between clinicopathologic factors and metastasis of RLNs in dMMR patients.ResultsIn univariate analysis,tumor size,differentiation,lymphovascular invasion,tumor deposit,pathologic T stage(pT),the number of negative lymph nodes(NLN)and the expression of the MSH6 protein were significantly associated with RLNs metastasis.What is more,all the patients with well differentiation tumors(15 patients)or staged pT1(13 patients)had no lymph node metastasis.Then,factors which could available before surgery were included in multivariate analysis,we found that tumor differentiation(OR=2.582,95%CI:1.57-4.27,P<0.001),pT(OR=3.78,95%CI:1.45-12.96,P=0.015)and the expression of MSH6 protein(OR=2.19,95%CI:1.16-4.40,P=0.021)were still significantly associated with RLNs metastasis.Different risk groups were divided by the above three factors and we found distinct difference for the number and distribution of RLNs metastasis between these subgroups,which provide some new thinking about prediction of regional lymph node metastasis and the range of surgery.ConclusionAs for CRC patients with dMMR,pT,differentiation and the expression of MSH6 were independent risk factors for RLNs metastasis.Evaluate these three factors before surgery may further increase the accuracy of prediction of RLNs metastasis,and help to make individual surgery strategy.