File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers

TitleGermline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers
Authors
KeywordsColorectal cancer
HNPCC
Microsatellite instability
Mismatch repair gene mutation
Promoter methylation
Issue Date2002
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2002, v. 21 n. 49, p. 7585-7592 How to Cite?
AbstractHigh-frequency microsatellite instability (MSI-H) results from deficiency in nucleotide mismatch repair. It contributes significantly to carcinogenesis in the human colorectal mucosa. Here we study 41 colorectal and three other HNPCC-related cancers with MSI-H to provide comprehensive information on the mechanisms of inactivation of the two major proteins involved, hMLH1 and hMSH2. Seventeen of the patients had family histories meeting the criteria for Bethesda grades 1, 2 or 3. Of these familial cases, 14 (83%) had early-onset disease, defined on the basis of diagnosis prior to the age of 50, but in three the disease was of late onset (>50 years). A second subset of 20 patients had early onset disease without family history. The remaining seven patients were selected to allow comparisons with sporadic, late-onset disease, the molecular basis of which has been extensively reported elsewhere. We stratified the tumours initially on the basis of hMLH1 or hMSH2 protein deficiency, detected by immunohistochemistry, and then by analysis of germline and somatic mutation, mRNA transcription, loss of heterozygosity (LOH) at the hMLH1 and hMSH2 loci, and methylation status in two regions of the hMLH1 promoter. The functional significance of several of these changes in the MSI-H tumours was confirmed by comparisons with 16 tumours with low-frequency microsatellite instability and 56 tumours with stable microsatellites. As anticipated, patients with family histories usually showed germline mutation of hMSH2 or hMLH1. In many cases the residual normal allele was silenced in their tumours by loss of heterozygosity (LOH). The small subset of late-onset, sporadic cases confirmed the preponderance in this group of biallelic hMLH1 promoter methylation. In the early-onset, apparently sporadic subset there were 11 tumours with hMLH1 deficiency, five with hMSH2 deficiency and four with no detectable abnormality in expression of either protein. These showed a complex mixture of lesions, including germline and somatic mutations, promoter methylation, LOH, suppression of wild-type RNA by as yet undiscovered mechanisms, or no detectable abnormality in any of these parameters. Evidence is presented to indicate that methylation in proximal region of the hMLH1 promoter is a more reliable correlate of transcriptional silencing in colorectal cancers than methylation in upstream region. These observations have significant implications for management of patients with MSI-H tumours.
Persistent Identifierhttp://hdl.handle.net/10722/88750
ISSN
2015 Impact Factor: 7.932
2015 SCImago Journal Rankings: 4.047
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYuen, STen_HK
dc.contributor.authorChan, TLen_HK
dc.contributor.authorHo, JWCen_HK
dc.contributor.authorChan, ASYen_HK
dc.contributor.authorChung, LPen_HK
dc.contributor.authorLam, PWYen_HK
dc.contributor.authorTse, CWen_HK
dc.contributor.authorWyllie, AHen_HK
dc.contributor.authorLeung, SYen_HK
dc.date.accessioned2010-09-06T09:47:28Z-
dc.date.available2010-09-06T09:47:28Z-
dc.date.issued2002en_HK
dc.identifier.citationOncogene, 2002, v. 21 n. 49, p. 7585-7592en_HK
dc.identifier.issn0950-9232en_HK
dc.identifier.urihttp://hdl.handle.net/10722/88750-
dc.description.abstractHigh-frequency microsatellite instability (MSI-H) results from deficiency in nucleotide mismatch repair. It contributes significantly to carcinogenesis in the human colorectal mucosa. Here we study 41 colorectal and three other HNPCC-related cancers with MSI-H to provide comprehensive information on the mechanisms of inactivation of the two major proteins involved, hMLH1 and hMSH2. Seventeen of the patients had family histories meeting the criteria for Bethesda grades 1, 2 or 3. Of these familial cases, 14 (83%) had early-onset disease, defined on the basis of diagnosis prior to the age of 50, but in three the disease was of late onset (>50 years). A second subset of 20 patients had early onset disease without family history. The remaining seven patients were selected to allow comparisons with sporadic, late-onset disease, the molecular basis of which has been extensively reported elsewhere. We stratified the tumours initially on the basis of hMLH1 or hMSH2 protein deficiency, detected by immunohistochemistry, and then by analysis of germline and somatic mutation, mRNA transcription, loss of heterozygosity (LOH) at the hMLH1 and hMSH2 loci, and methylation status in two regions of the hMLH1 promoter. The functional significance of several of these changes in the MSI-H tumours was confirmed by comparisons with 16 tumours with low-frequency microsatellite instability and 56 tumours with stable microsatellites. As anticipated, patients with family histories usually showed germline mutation of hMSH2 or hMLH1. In many cases the residual normal allele was silenced in their tumours by loss of heterozygosity (LOH). The small subset of late-onset, sporadic cases confirmed the preponderance in this group of biallelic hMLH1 promoter methylation. In the early-onset, apparently sporadic subset there were 11 tumours with hMLH1 deficiency, five with hMSH2 deficiency and four with no detectable abnormality in expression of either protein. These showed a complex mixture of lesions, including germline and somatic mutations, promoter methylation, LOH, suppression of wild-type RNA by as yet undiscovered mechanisms, or no detectable abnormality in any of these parameters. Evidence is presented to indicate that methylation in proximal region of the hMLH1 promoter is a more reliable correlate of transcriptional silencing in colorectal cancers than methylation in upstream region. These observations have significant implications for management of patients with MSI-H tumours.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/oncen_HK
dc.relation.ispartofOncogeneen_HK
dc.subjectColorectal canceren_HK
dc.subjectHNPCCen_HK
dc.subjectMicrosatellite instabilityen_HK
dc.subjectMismatch repair gene mutationen_HK
dc.subjectPromoter methylationen_HK
dc.subject.meshAdaptor Proteins, Signal Transducingen_HK
dc.subject.meshBase Pair Mismatchen_HK
dc.subject.meshBase Sequenceen_HK
dc.subject.meshCarrier Proteinsen_HK
dc.subject.meshColorectal Neoplasms - geneticsen_HK
dc.subject.meshColorectal Neoplasms, Hereditary Nonpolyposis - geneticsen_HK
dc.subject.meshDNA Methylationen_HK
dc.subject.meshDNA Primersen_HK
dc.subject.meshDNA-Binding Proteinsen_HK
dc.subject.meshGerm-Line Mutationen_HK
dc.subject.meshHumansen_HK
dc.subject.meshImmunohistochemistryen_HK
dc.subject.meshLoss of Heterozygosityen_HK
dc.subject.meshMutS Homolog 2 Proteinen_HK
dc.subject.meshNeoplasm Proteins - geneticsen_HK
dc.subject.meshNuclear Proteinsen_HK
dc.subject.meshPromoter Regions, Geneticen_HK
dc.subject.meshProto-Oncogene Proteins - geneticsen_HK
dc.subject.meshTranscription, Geneticen_HK
dc.titleGermline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancersen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0950-9232&volume=21&issue=49&spage=7585&epage=7592&date=2002&atitle=Germline,+somatic+and+epigenetic+events+underlying+mismatch+repair+deficiency+in+colorectal+and+HNPCC-related+cancersen_HK
dc.identifier.emailChan, TL: tlchan@hku.hken_HK
dc.identifier.emailChung, LP: lpchung@hkucc.hku.hken_HK
dc.identifier.emailLeung, SY: suetyi@hku.hken_HK
dc.identifier.authorityChan, TL=rp00418en_HK
dc.identifier.authorityChung, LP=rp00249en_HK
dc.identifier.authorityLeung, SY=rp00359en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/sj.onc.1205968en_HK
dc.identifier.pmid12386821-
dc.identifier.scopuseid_2-s2.0-0037168207en_HK
dc.identifier.hkuros81975en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037168207&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume21en_HK
dc.identifier.issue49en_HK
dc.identifier.spage7585en_HK
dc.identifier.epage7592en_HK
dc.identifier.isiWOS:000178618200014-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridYuen, ST=7103160927en_HK
dc.identifier.scopusauthoridChan, TL=7402687537en_HK
dc.identifier.scopusauthoridHo, JWC=25925854200en_HK
dc.identifier.scopusauthoridChan, ASY=7403168075en_HK
dc.identifier.scopusauthoridChung, LP=24315879100en_HK
dc.identifier.scopusauthoridLam, PWY=7202365931en_HK
dc.identifier.scopusauthoridTse, CW=36958765600en_HK
dc.identifier.scopusauthoridWyllie, AH=35474548100en_HK
dc.identifier.scopusauthoridLeung, SY=7202044886en_HK

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats