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Conference Paper: Study of the mechanisms underlying heritable germline epimutation of MSH2 in a Hereditary Nonpolyposis Colorectal Cancer family

TitleStudy of the mechanisms underlying heritable germline epimutation of MSH2 in a Hereditary Nonpolyposis Colorectal Cancer family
Authors
Issue Date2007
PublisherAmerican Association for Cancer Research.
Citation
The 98th Annual Meeting of the American Association for Cancer Research (AACR 2007), Los Angeles, CA, 14-18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 2844 How to Cite?
AbstractColorectal cancer (CRC) is one of the most common cancers world-wide. Among various forms of familial cancers, Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is the most frequent type of hereditary cancer syndromes. It is well known that inactivation of DNA mismatch repair (MMR) genes are responsible for HNPCC. Germline mutations in either the MSH2 or the MLH1 genes can be detected in the majority of HNPCC patients. Alternatively, methylation of the MLH1 promoter in the germline have been observed in a few individuals with HNPCC. More recently, we have first identified a family with inheritance in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene promoter, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal (CRC) or endometrial cancers, all with microsatellite instability and MSH2 protein loss [Chan et al Nat Genet 2006]. To further elucidate the underlying mechanism of this germline epimutation, we have performed linkage analysis using microsatellite markers flanking the MSH2 gene. Based on the presence of recombination events, we have successfully narrowed down the chromosomal region to less than 20Mb that is linked with the occurrence of germline MSH2 methylation. Methylation status of the genes with CpG island within this region was examined. The promoter of all genes located upstream of MSH2 were unmethylated. The MSH6 gene which is located downstream of MSH2 also showed no sign of methylation. Our result suggests a possible existence of a cis-acting element that may contribute to the MSH2 methylation. Further study of this chromosomal region may reveal novel mechanisms involved in the regulation of methylation in humans.
Persistent Identifierhttp://hdl.handle.net/10722/104676
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorChan, TLen_HK
dc.contributor.authorYuen, STen_HK
dc.contributor.authorLo, MWSen_HK
dc.contributor.authorLee, TYHen_HK
dc.contributor.authorKong, CKen_HK
dc.contributor.authorChan, YWen_HK
dc.contributor.authorTsui, WYen_HK
dc.contributor.authorLi, VSWen_HK
dc.contributor.authorChan, ASYen_HK
dc.contributor.authorLeung, SYen_HK
dc.date.accessioned2010-09-25T22:02:49Z-
dc.date.available2010-09-25T22:02:49Z-
dc.date.issued2007en_HK
dc.identifier.citationThe 98th Annual Meeting of the American Association for Cancer Research (AACR 2007), Los Angeles, CA, 14-18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 2844-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/104676-
dc.description.abstractColorectal cancer (CRC) is one of the most common cancers world-wide. Among various forms of familial cancers, Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is the most frequent type of hereditary cancer syndromes. It is well known that inactivation of DNA mismatch repair (MMR) genes are responsible for HNPCC. Germline mutations in either the MSH2 or the MLH1 genes can be detected in the majority of HNPCC patients. Alternatively, methylation of the MLH1 promoter in the germline have been observed in a few individuals with HNPCC. More recently, we have first identified a family with inheritance in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene promoter, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal (CRC) or endometrial cancers, all with microsatellite instability and MSH2 protein loss [Chan et al Nat Genet 2006]. To further elucidate the underlying mechanism of this germline epimutation, we have performed linkage analysis using microsatellite markers flanking the MSH2 gene. Based on the presence of recombination events, we have successfully narrowed down the chromosomal region to less than 20Mb that is linked with the occurrence of germline MSH2 methylation. Methylation status of the genes with CpG island within this region was examined. The promoter of all genes located upstream of MSH2 were unmethylated. The MSH6 gene which is located downstream of MSH2 also showed no sign of methylation. Our result suggests a possible existence of a cis-acting element that may contribute to the MSH2 methylation. Further study of this chromosomal region may reveal novel mechanisms involved in the regulation of methylation in humans.-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research.-
dc.relation.ispartofCancer Researchen_HK
dc.titleStudy of the mechanisms underlying heritable germline epimutation of MSH2 in a Hereditary Nonpolyposis Colorectal Cancer familyen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailChan, TL: tlchan@hku.hken_HK
dc.identifier.emailYuen, ST: styuen@hkucc.hku.hken_HK
dc.identifier.emailLo, MWS: sept15elle@hotmail.comen_HK
dc.identifier.emailLee, TYH: tracy.tracylee@gmail.comen_HK
dc.identifier.emailChan, YW: chanywa@hku.hken_HK
dc.identifier.emailTsui, WY: wendy@pathology.hku.hken_HK
dc.identifier.emailLi, VSW: vswli81@graduate.hku.hken_HK
dc.identifier.emailChan, ASY: asychan@HKUCC.hku.hken_HK
dc.identifier.emailLeung, SY: suetyi@hkucc.hku.hken_HK
dc.identifier.authorityLeung, SY=rp00359en_HK
dc.identifier.hkuros126943en_HK
dc.identifier.volume67-
dc.identifier.issue9S-
dc.identifier.spage2844-

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