Expression And Clinical Significance Of Mismatch Repair Genes In Chinese Suspected HNPCC

【Objective】 Hereditary non-polyposis colorectal cancer (HNPCC) is anautosomal dominant inheritance syndrome. HNPCC is the most common hereditaryvariant of colorectal cancer (CRC), which accounts for2-5%of all newly diagnosedcases of CRCs, mainly due to mutations in mismatch repair (MMR) genes. There areseveral diagnostic standards which have been used to identify patients with a possibleDNA mismatch repair defect (HNPCC). Our study aims to discuss risk factors and theexpression of MLH1, MSH2, MSH6, PMS2in suspected HNPCC patients in China, andto evaluate the value of those diagnostic standards and IHC in screening suspectedHNPCC, so as to find a simple, fast and precise strategy for screening HNPCC.【Methods】Suspected HNPCC patients who received surgery therapy in ourhospital from2002.1to2009.12are selected according to revised Bethesda guideline.We detecte the expression of MLH1, MSH2, MSH6and PMS2in colorectal cancertissue by immunohistochemistry. To analyze the relationship between MMR expressionand the clinicopathologic index of CRC by χ2test and between MMR expression andOS by Kaplan-Meier. These results are analyzed by SPSS16.0statistical softwarepackage, a P-value less than0.05were considered significant.【Results】1. Loss of MMR immunohistochemical staining was observed in59.7%of patientsthat met the revised Bethesda guideline. The expression of MMR was significantcorrelation with age, location, T stage and TNM stage (P<0.05). Until the destination ofstudy, there were10cases dead (the average survival was27.3±46.2months). The5-year survival rate is93%and78%for MMR-defective and MMR-intact tumorsrespectively. MMR-defective predicted a significantly better OS in proximal coloncancer, poor differentiation cancer, mixed-type adenocarcinoma and T3-4stage cancer subgroups (P=0.041、P=0.005、P=0.001、P=0.039).2. Loss of MMR immunohistochemical staining was observed in87.5%of patientsthat met the Amsterdam Ⅱ criteria (group A) and in54.2%of patients that met theChinese HNPCC criteria (group B), and in50%of patients that met the Bethesdaguideline only (group C). There was significant difference in the negative expressionrate between group A and B, also between group A and C.3. The negative expression rate of MLH1was15.3%. The expression of MLH1was not related with clinicopathologic factors. The negative expression rate of MSH2was34.7%. The expression of MSH2was significant correlation with age (P=0.001).The negative expression rate of MSH6was23.6%. The expression of MSH6wassignificant correlation with type and MPC (P=0.003，P=0.024).4. The negative expression rate of PMS2was34.7%of all. The expression ofPMS2was significant correlation with age and location (P=0.033，P=0.001). AddingPMS2staining led to the identification of an additional12.5%of suspected mutationcarriers.【Conclusions】Evident family history of HNPCC-relative cancers, young age,proximal colon cancer, TNM Ⅰ-Ⅱ stage and T3-4stage are risk factors of suspectedHNPCC patients in China. Revised Bethesda guideline is recommended to be used inscreening suspected HNPCC patients, combining MSI test and IHC test. Routine IHCdiagnostics for HNPCC should include MLH1, MSH2, MSH6and PMS2staining.