Chinese Hereditary Non-polyposis Colorectal Cancer (hnpcc) Mutation Screening And Data Analysis

Hereditary Non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. It is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs. This disease mainly due to MLH1 and MSH2 gene functional defects in DNA mismatch repair (MMR) system. Most (90%) of the mutations were found in two MMR genes, MLH1 and MSH2. The International Society of Gastrointestinal Hereditary Tumors (InSiGHT) set up a database about the mutations which are associated with HNPCC (http://www.insight-group.org/mutations/). The database collected a large number of mutation data, and are widly used.Ninety-eight unrelated suspect HNPCC families were studied from 1994 to 2008 in Shanghai Cancer Hospital of Fudan University, all of which fulfilled Bethesda criteria. The young suspect patients (diagnosis age≤40 years old) were approximately one-third of all the patients. The ratio of the patients diagnosed before 50 years old was 68.4%, which showed strong early onset feature. Most of the tumors in suspect HNPCC patients were left side, especually rectal cancer. Right side tumors were less then left (64.75 vs.35.3%). Among the ten families with mutations, there were totally 20 extracolorectal tumors. Gastric cancer and endometrial cancer were the most—25%. The high incidence of gastric cancer might be one of the features of Asian HNPCC patients. Shanghai Cancer Hospital of Fudan University proposed "Fudan Recommend Criteria" to diagnose HNPCC, the sensetivity of which was higher than Amsterdam criteria. The families fulfilled Fudan Recommend Criteria and the families fulfilled Amsterdam criteria have similar clinicopathologic features. It shows that Fudan Recommend Criteria played an important role in diagnosing Chinese HNPCC families.Among the 98 suspect HNPCC patients, a total of eleven MLH1 or MSH2 mutations were found in ten patients (11%). Four were missense mutations (MLH1 c.655A>G and c.2042C>T; MSH2 c.23C>T and C.1168C>T), two were frameshift (MLH1 c.157₁60delGAGG and c.2157dupT), one was in the promoter area of MLH1 gene c.-64G>T and one aberrant splicing (MLH1 c.1989G>A). Most of the mutations were missense mutations, which also proved that the missense mutations are the most common type in Chinese HNPCC patients. Three novel mutations which had never been reported were founded. Two of them were frameshift mutations in MLH1 gene and resulted in coding early termination, which were all considered as pathologic mutations. The other one was in promoter area of MLH1 gene (c.-64G>T), which might cause functional defect of MLH1 portein and associated with HNPCC. Among the 98 unrelated probands, four patients harbored one same mutation (MSH2 c.1168C>T, dsSNP17224367). We suggested this mutation was hotspot in East Asian, might be the "Founder mutation". Further study was needed to prove this.According to the analysis of MLH1 and MSH2 gene mutations in InSiGHT database, we found that the distributions of mutation individuals in exon 1,17 and 19 of MLH1 gene and in exon 2 of MSH2 gene showed significant differences between white race and yellow race. The distributions of mutation types in exon 2,7 and 18 of MLH1 and exon 10 and 16 of MSH2 showed significant differences between two race groups. Some mutations were only found in yellow race, for example, three mutations in MLH1 gene (c.1453G>C, c.1742C>T and c.1758dupC) and two mutations in MSH2 gene (c.1255C.A and c.1886A>G). Three mutations (c.649C>T, c.1625A>T and c.1721T>C) in MLH1 and five mutations (c.23C>T, c.2211-6T>C, c.187dupG, c.505A>G and c.1168C>T) in MSH2 have much higher frequency in yellow race than those in white race, which showed high race preference. All of the conclusions implied that mutaitons in MLH1 and MSH2 gene had significant differences between yellow race and white race. The exons and mutations which showed significant differences should be paid more attention in further study.