Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer.
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.
Liu
Hong-Xu
HX
Department of Thoracic Surgery, First Hospital, China Medical University, Shenyang 110001, Liaoning Province, China. hongxuliu@yahoo.com
Li
Yu
Y
Jiang
Xue-Dong
XD
Yin
Hong-Nian
HN
Zhang
Lin
L
Wang
Yu
Y
Yang
Jun
J
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
D002352:Carrier Proteins; D017931:DNA Primers; C403623:MLH3 protein, human; D000070956:MutL Proteins