Clinical features and mismatch repair gene mutation screening in Chinese patients with hereditary nonpolyposis colorectal carcinoma

AIM:Hereditary nonpolyposis colorectal cancer (HNPCC)is an autosomal dominantly-inherited cancer-susceptibilitysyndrome that confers an increased risk for colorectalcancer and a variety of other tumors at a young age.It hasbeen associated with germline mutations in five mismatchrepair (MMR) genes (hMSH2,hMLH1,hPMS1,hPMS2,andhMSH6/GTBP).The great majority of germline mutationswere found in hMSH2 and hMLHI.The purpose of thisstudy was to analyze the clinical features of Chinese HNPCCpatients and to screen hMSH2 and hMLH1 gene mutations.METHODS:Twenty-eight independent Chinese familieswere collected,of which 15 met Amsterdam criteria Ⅰ and13 met the Japanese clinical diagnosis criteria.The datawere recorded including sex,site of colorectal cancer (CRC),age of diagnosis,history of synchronous and/ormetachronous CRC,instance of extracolonic cancers,andhistopathology of tumors.Peripheral blood samples werecollected from all pedigrees after formal written consentswere signed.PCR and denaturing high-performance liquidchromatography (DHPLC) were used to screen the codingregions of hMSH2 and hMLH1 genes.The samples showingabnormal DHPLC profiles were sequenced by a 377 DNAsequencer.RESULTS:One hundred and seventy malignant neoplasmswere found in one hundred and twenty-six patients (multiplecancer in twenty-three),including one hundred and twenty-seven CRCs,fifteen gastric,seven endometrial,and fiveesophageal cancers.Seventy-seven point eight percent ofthe patients had CRCs,sharing the features of earlyoccurrence (average age of onset,45.9 years) and of theright-sided predominance reported in the literature.InChinese HNPCC patients,gastric cancer occurred morefrequently,accounting for 11.9% of all cancers patientsand ranking second in the spectrum of HNPCC predisposingcancers.Synchronous CRCs occurred less frequently,onlyaccounting for 3.1% of the total CRCs.Twenty percent ofthe colorectal patients had metachronous CRCs within10 years after Operation.Eight hMSH2 or hMLH1 genesequence variations were found in twelve families,includingthe first Mongolian kindred with a hMSH2 gene mutation.CONCLUSION:HNPCC is characterized by an early-age onset,proximal predominance of CRC,multiple metachronousCRCs,and an excess of extra-colonic cancers.Frequentgastric cancer occurrence and less synchronous CRCs arethe remarkable features in Chinese HNPCC patients.DHPLCis a powerful tool in hMSH2 and hMLH1 gene mutationscreening,hMLH1 gene mutations,especially of the firstnine exons,have been found more common than hMSH2gene mutations in Chinese patients.Three of sevenmutations have been found to be novel,and the germlineG204X nonsense mutation in the third exon of hMSH2 hasbecome the first MMR gene mutation found in ChineseMongolian people.