The Expression Of MMR Protein In Hereditary Nonpolyposis Colorectal Cancer

HNPCC is an autosomal and dominantly inherited cancer predisposition caused by a constitutional defect in a MMR gene.lt is estimated to cause 5-15% of colorectalcancer.HNPCC patients usually develop tumors at a young age and have a tendency for synchronous or metachronous tumors. The phenotype of HNPCC features an excess of early onset CRC with a propensity to involve the proximal (right-sided) colon, and a variety of extracolonic cancers,particularly carcinomas of the endometrium, ovary, stomach, small bowel, pancreas, hepatobiliary tract, brain and upper uroepithelium of ureter and renal pelvis, in addition to skin lesions.So it is important to identify HNPCC patients and its kindreds so that routine detection and effective treatment can be conducted as early as possible. Because no macroscopic or microscopic features are exclusively associated with HNPCC,the identification of mutations in MMR genes serves as the gold standard in diagnosing HNPCC.There areat least six genes associated with this predisposition: hMLH 1, hMSH2, hPMS 1, hPMS2, hMSH3 and h MSH6. Most of the mutations occurred in hMLH 1 and hMSH2,and some mutations existed in hMSH6 and hPMS2. When MMR was mutated, the expression of MMR protein may decline and disappear or truncate. Immunohistochemistry showed the expression of MMR protein was missing. In this study, we used immunohistochemistry to detect the expression of hMLH1, hMSH2, hMSH6 and hPMS2 proteins in Yunnan HNPCC pedigrees.[Objective]1. To observe the lack expression of hMLH1, hMSH2, hMSH6 and hPMS2 proteins in HNPCC pedigrees.2.To compare the sensitivity of the screening HNPCC between hMLH1, hMSH2 antibody and hMLH1, hMSH2, hMSH6 and hPMS2 antibody in immunohistochemistry.3. To determine the consistency of MMR protein expression in a pedigrees with 2 cases or more than 2 cases tumor.4. To investigate the value of immunohistochemical detection in screening HNPCC pedigrees.[Methods]From october 2007 to October 2009, we collected 13 HNPCC pedigrees and 19 cases tumor tissue in the First and The Third Affiliated Hospital of Kunming Medical College which were screened by clinical and pathological analysis.And normal colon mucosal tissues were collected as control. We detected the expression of hMLH1, hMSH2, hMSH6 and hPMS2 protein in Yunnan HNPCC pedigrees tumor by immunohistochemical method (SP method)[Results]There were identical expression of MMR protein in a family with two cases or more than 2 cases. In the 13 pedigrees, the expression loss rates of MLH1, MSH2, PMS2, and MSH6 protein were 30.77%(4/13),38.46%(5/13),23.08%(3/13), 23.08%(3/13).And in these tumor tissues case of lack of MMR protein,2 cases were loss of expression of MLH1 and PMS2 protein at the same time; 1 cases were loss of expression of MSH2 and MSH6 at the same time.The total expression loss rates of four MMR protein was 92.30%. The sensitivity to screen HNPCC pedigrees with MLH1 and MSH2 antibodies only was 69.23%(9/13), but the sensitivity to screen HNPCC pedigrees with MLH1, MSH2, PMS2, and MSH6 antibodies was 92.30% (12/13).[Conclusion]1. There were lost expression of hMLH1, hMSH2, hPMS2, and hMSH6 protein in the tumor tissue of HNPCC pedigrees.2. Detection of hMLHl and hMSH2 protein expression by immunohistochemistry contributed to diagnosis of HNPCC, but the sensitivity is not high enough. After added to hPMS2 and hMSH6 antibody,the sensitivity were significantly increased.3.The probands and the other sick in HNPCC pedigrees had the same MMR protein expression.4. The immunohistochemical method combined with hMLH1, hMSH2, hPMS2, and hMSH6 antibody could screen HNPCC families.