title: Novel DNA variants and mutation frequencies of hMLH1 and hMSH2 genes in colorectal cancer in the Northeast China population.
abstract: Research on hMLH1 and hMSH2 mutations tend to focus on Lynch syndrome (LS) and LS-like colorectal cancer (CRC). No studies to date have assessed the role of hMLH1 and hMSH2 genes in mass sporadic CRC (without preselection by MSI or early age of onset). We aimed to identify novel hMLH1 and hMSH2 DNA variants, to determine the mutation frequencies and sites in both sporadic and LS CRC and their relationships with clinicopathological characteristics of CRC in Northeast of China. 452 sporadic and 21 LS CRC patients were screened for germline and somatic mutations in hMLH1 and hMSH2 genes with PCR-SSCP sequencing. We identified 11 hMLH1 and seven hMSH2 DNA variants in our study cohort. Six of them were novel: four in hMLH1 gene (IVS8-16 A>T, c.644 GAT>GTT, c.1529 CAG>CGG and c.1831 ATT>TTT) and two in hMSH2 gene (-39 C>T, insertion AACAACA at c.1127 and deletion AAG at c.1129). In sporadic CRC, germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 15.59% and 17.54%, respectively (p = 0.52). Germline mutations present in hMLH1 and hMSH2 genes were 5.28% and 10.78%, respectively (p<0.01). Somatic mutations in hMLH1 and hMSH2 genes were 6.73% and 11.70%, respectively (p = 0.02). In LS CRC, both germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 28.57%. The most prevalent germline mutation site in hMSH2 gene was c.1168 CTT>TTT (3.90%), a polymorphism. Somatic mutation frequency of hMLH1/hMSH2 gene was significantly different in proximal, distal colon and rectal cancer (p = 0.03). Our findings elucidate the mutation spectrum and frequency of hMLH1 and hMSH2 genes in sporadic and LS CRC, and their relationships with clinicopathological characteristics of CRC.
authors.affiliation: Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, People's Republic of China.
authors.forename: Fulan
authors.initials: F
authors.lastname: Hu
authors.forename: Dandan
authors.initials: D
authors.lastname: Li
authors.forename: Yibaina
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yao
authors.forename: Wencui
authors.initials: W
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Liang
authors.forename: Chunqing
authors.initials: C
authors.lastname: Lin
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Ren
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
authors.forename: Shuying
authors.initials: S
authors.lastname: Li
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Binbin
authors.initials: B
authors.lastname: Cui
authors.forename: Xinshu
authors.initials: X
authors.lastname: Dong
authors.forename: Suli
authors.initials: S
authors.lastname: Tian
authors.forename: Yashuang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D002681:China; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D047368:Tumor Burden
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein