title: Molecular analysis of MLH1 variants in Chinese sporadic colorectal cancer patients.
abstract: Single nucleotide polymorphisms (SNPs) in mismatch repair genes, especially in the MLH1 gene, are closely associated with susceptibility to hereditary nonpolyposis colorectal cancer. However, few relevant findings are available regarding the association between sporadic colorectal cancer (SCRC) and SNPs of MLH1 in Chinese patients. Therefore, the present study aimed to describe the pathogenic association between three important MLH1 polymorphisms and SCRC in the Chinese population. Peripheral blood samples from 156 SCRC patients and 311 healthy controls were collected. DNA was purified from peripheral blood, and the V384D, R217C, and I219V polymorphisms were evaluated using high-resolution melting analysis and direct sequencing. The association between the three important MLH1 polymorphisms and clinical pathological features of the SCRC patients was analyzed. In addition, PMS2-MLH1 protein interactions were determined by co-immunoprecipitation (Co-IP) to determine the protein functional alteration induced by these SNPs. Among the three polymorphisms, V384D was significantly associated with the risk of SCRC (OR = 31.36, P < 0.0001). The allele frequencies were 4.81 and 0.16% in the SCRC group. No association was found between SCRC and R217C, or between SCRC and I219V. Moreover, the allele frequency of R217C was significantly higher in the SCRC patients younger than 60 years than in those older than 60 years. Co-IP showed that the MLH1 R217C, V384D, and I219V variants had relative binding abilities with PMS2 of 0.59, 0.70, and 0.80, respectively, compared with the wild-type. These findings suggest that MLH1 V384D could be a promising genetic marker for susceptibility to SCRC.
authors.affiliation: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.|Digestive Endoscopy Center, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: H X
authors.initials: HX
authors.lastname: Peng
authors.affiliation: Central Laboratory, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Laboratory Medicine, Jinshan Hospital, Fudan University, Shanghai, China.
authors.forename: R
authors.initials: R
authors.lastname: Yang
authors.affiliation: Digestive Endoscopy Center, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y M
authors.initials: YM
authors.lastname: Chu
authors.affiliation: Digestive Endoscopy Center, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: D M
authors.initials: DM
authors.lastname: Yang
authors.affiliation: Digestive Endoscopy Center, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Digestive Endoscopy Center, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: F L
authors.initials: FL
authors.lastname: Zhou
authors.affiliation: Central Laboratory, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: W Z
authors.initials: WZ
authors.lastname: Ma
authors.affiliation: Central Laboratory, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Guan
authors.affiliation: Department of Clinical Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
authors.forename: Z D
authors.initials: ZD
authors.lastname: Jin
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002681:China; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000378:metabolism; D000070957:MutL Protein Homolog 1 / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding
chemical_list: C501486:MLH1 protein, human; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1