首页|Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients

Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients

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AIM:To investigate the protein expression profile of mismatch repair (MMR) genes in suspected cases of Lynch syndrome and to characterize the associated germline mutations.METHODS:Immunohistochemical analysis of tumor samples was performed to determine the protein expression profile of MMR protein.Germline mutation screening was carried out on peripheral blood samples.The entire exon regions of MLH1 and MSH2 genes were amplified by polymerase chain reaction,screened by denaturing high performance liquid chromatography (dHPLC) and analyzed by DNA sequencing to characterize the germline mutations.RESULTS:Three out of 34 tissue samples (8.8％) and four out of 34 tissue samples (11.8％) showed loss of nuclear staining by immunohistochemistry,indicating the absence of MLH1 and MSH2 protein expression in carcinoma cells,respectively.dHPLC analysis followed by DNA sequencing showed these samples to have germline mutations of MSH2 gene.However,no deleterious mutations were identified in any of the 19 exons or coding regions of MLH1 gene,but we were able to identify MLH1 promoter polymorphism,-93G ＞A (rs1800734),in 21 out of 34 patients (61.8％).We identified one novel mutation,transversion mutation c.2005G ＞ C,which resulted in a missense mutation (Gly669Arg),a transversion mutation in exon 1,c.142G ＞ T,which resulted in a nonsense mutation (Glu48Stop)and splice-site mutation,c.2006-6T ＞ C,which was adjacent to exon 13 of MSH2 gene.CONCLUSION:Germline mutations were identified in four Malaysian Lynch syndrome patients.Immunohistochemical analysis of tumor tissue proved to be a good pre-screening test before proceeding to germline mutation analysis of DNA MMR genes.

Denaturing high performance liquid chromatographyDNA sequencingGermline mutationMismatch repair genesImmunohistochemistryLynch syndrome

Mohd Nizam Zahary、Gurjeet Kaur、Muhammad Radzi Abu Hassan、Harjinder Singh、Venkatesh R Naik、Ravindran Ankathil

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Human Genome Centre, School of Medical Sciences, University Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia

Institute for Research in Molecular Medicine,University Sains Malaysia, 11800 Penang, Malaysia

Internal Medicine Department, Hospital Alor Star, 05460 Alor Star, Kedah, Malaysia

Department of Medicine, Hospital Queen Elizabeth, 88586 Kota Kinabalu, Sabah, Malaysia

Department of Pathology, School of Medical Sciences, University Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia

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USM Research University Grant

1001/CIPPT/813005

2012

10.3748/wjg.v18.i8.814

世界胃肠病学杂志(英文版)
太原消化病研治中心

世界胃肠病学杂志(英文版)

SCI
影响因子：1.001
ISSN：1007-9327
年,卷(期)：2012.18(8)
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