title: Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer.
abstract: OBJECTIVE
  To shed light on the possible role of mismatch repair gene Mlh3 in familial esophageal cancer (FEC).
  
  
  METHODS
  A total of 66 members from 10 families suggestive of a genetic predisposition to hereditary esophageal cancer were screened for germline mutations in Mlh3 with denaturing high performance liquid chromatography (DHPLC), a newly developed method of comparative sequencing based on heteroduplex detection. For all samples exhibiting abnormal DHPLC profiles, sequence changes were evaluated by cycle sequencing. For any mutation in family members, we conducted a segregation study to compare its prevalence in sporadic esophageal cancer patients and normal controls.
  
  
  RESULTS
  Exons of Mlh3 in all samples were successfully examined. Overall, 4 missense mutations and 3 polymorphisms were identified in 4 families. Mlh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no sufficient evidence supporting the monogenic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families.
  
  
  CONCLUSIONS
  Mlh3 is a high risk gene with a reduced penetrance in some families. However, it acts as a low risk gene for esophageal cancer in most families. Mutations of Mlh3 may work together with other genes in an accumulated manner and result in an increased risk of esophageal tumor. DHPLC is a robust and sensitive technique for screening gene mutations.
authors.affiliation: Department of Thoracic Surgery, First Hospital, China Medical University, Shenyang 110001, Liaoning Province, China. hongxuliu@yahoo.com
authors.forename: Hong-Xu
authors.initials: HX
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Xue-Dong
authors.initials: XD
authors.lastname: Jiang
authors.forename: Hong-Nian
authors.initials: HN
authors.lastname: Yin
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair; D004938:Esophageal Neoplasms / Q000235:genetics*; D005091:Exons; D005192:Family Health; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D000070956:MutL Proteins; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013696:Temperature
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; C403623:MLH3 protein, human; D000070956:MutL Proteins