title: Clinical features and mismatch repair genes analyses of Chinese suspected hereditary non-polyposis colorectal cancer: a cost-effective screening strategy proposal.
abstract: China has the largest numbers of hereditary non-polyposis colorectal cancer (HNPCC) patients based on its population of 1.4 billion. However, the clinical data and mismatch repair (MMR) gene analyses have been limited. Here we performed microsatellite instability (MSI) and immunohistochemistry (IHC) analyses on a series of patients with a high-risk for HNPCC: 61 patients with family histories fulfilling Amsterdam criteria II (ACII-HNPCC) or suspected HNPCC criteria (S-HNPCC), and 106 early onset colorectal cancer (CRC) patients. Sixty late-onset CRC patients were used as control. Methylation of the hMLH1 promoter was analyzed on tumors lacking hMLH1 expression. MMR germ-line mutations were screened on patients with tumors classified as MSI-H/L or negative for IHC. We identified 27 germ-line MMR variants in the 167 patients with a high-risk for HNPCC while only one germ-line mutation in hMSH6 was found in the late-onset CRC group. Of those, 23 were pathogenic mutations. The high incidence of gastric and hepatobiliary cancers coupled with the increasing number of small families in China reduces the sensitivity (43.5%, 30.4%) and positive predictive value (PPV) (45.5%, 17.9%) of the ACII- or S-HNPCC criteria. MSI or IHC testing are highly sensitive in detecting pathogenic mutations (sensitivities = 91.3% and 95.6%, respectively), but the PPVs are quite low (25.6% and 27.8%, respectively). Considering that all 12 tumors with pathogenic mutations in hMLH1 also showed promoter unmethylation, the sensitivity of IHC in conjunction with hMLH1 promoter methylation analysis is not reduced, but the PPV was increased from 27.8% to 61.1%, and the total cost was greatly reduced.
authors.affiliation: Department of Medical Genetics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hong-Li
authors.initials: HL
authors.lastname: Yan
authors.forename: Li-Qiang
authors.initials: LQ
authors.lastname: Hao
authors.forename: Hei-Ying
authors.initials: HY
authors.lastname: Jin
authors.forename: Qing-He
authors.initials: QH
authors.lastname: Xing
authors.forename: Geng
authors.initials: G
authors.lastname: Xue
authors.forename: Qian
authors.initials: Q
authors.lastname: Mei
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Shu-Han
authors.initials: SH
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics*; D002681:China; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D003362:Cost-Benefit Analysis; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005820:Genetic Testing / Q000191:economics / Q000379:methods*; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein