Mismatch Repair Gene And Its Detectionmethod Study On The Diagnosis Value Of HNPCC

Background and ObjectiveHereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant genetic disease caused by inactivating mutations of DNA mismatch repair (MMR) genes and accounts for approximately5%to15%of all colorectal cancers. About2/3of the person in MMR-defect family with HNPCC-related diseases, male family members are more susceptible to colorectal cancer before the age of50and the risk of endometrial cancer in women was significantly higher than the general person. MMR proteins contribute to maintaining the accuracy and integrity of DNA replication by repairing the unpaired and mispaired bases in course of DNA replication and damage through formation of multimeric complexes. Studies demonstrated that the DNA mismatch repair system consists of at least six genes: hMLH1, hMSH2, hMSH3, hMSH6, hPMSl and hPMS2. Inactivation of hMLH1and hMSH2genes occurs most frequently which accounts for more than90%in the process of carcinogenesis followed by hMSH6and hPMS2. Therefore, this study mainly focuses on hMLHl and hMSH2. MMR genes defects lead to activation of oncogenes and inactivation of tumor suppressor genes and subsequently results in carcinogenesis. So, it is very important to screen the mutation of MMR genes using types of effective approaches and thus provide early intervention for patients. This also helps to improve prognosis of patients.The objectives of this study are detecting the loss of hMLHl and hMSH2expression in different HNPCC patients and studying mutation rate of MMR in HNPCC family. To investigate the values of immunohistochemistry (IHC) and MSI in detection and protection of family HNPCC.Methods26HNPCC patients in Surgical Oncology of our hospital were randomly selected from Feb.2009to Nov.2011and13healthy volunteers were recruited as normal control. IHC and MSI were performed to detect the expression of hMLHl and hMSH2in each group and corresponding family.Results4families of26patients complying with the Amsterdam criteria,5families complying with the Bethesda Guidelines,13families fulfilling the Chinese HNPCC criteria and4families with suspected HNPCC. IHC data showed that the absence rate of protein in HNPCC families is90.9%, in suspected HNPCC families is75.0%while the normal control is7.7%. There is a significant difference between HNPCC group and normal group (p<0.05), but there is no difference between HNPCC and suspected HNPCC groups. Absence rate of hMLHl and hMSH2in HNPCC families, suspected HNPCC families and control group are88.5%,50.0%,0.0%,90.0%,25.0%,0.0%respectively. And the absence rate of proteins in HNPCC was significantly different from suspected HNPCC and control groups (p<0.05). MSI-H and MSI-L results of HNPCC, suspected HNPCC and control groups were86.4%,25.0%,0.0%,13.6%,50.0%7.7%, MSI-H results indicated that HNPCC have a statistic difference from suspected and normal groups (p<0.05), while suspected HNPCC group showed a significant difference in MSI-L results compared with HNPCC and normal groups (p<0.05).ConclusionMMR genes are convincingly associated with HNPCC and we can detect the gene deficiency by IHC method. The sensitivity of IHC is better than MSI. The IHC can be widely used in genetic screening for HNPCC due to its simple method and easy operation for researchers. And this will help us detect the mutation much earlier and thus improve the prognosis of patients.