Publication:
Epigenetic inactivation of a cluster of genes flanking MLH1 in microsatellite-unstable colorectal cancer

dc.contributor.author Hitchins, Megan P. en_US
dc.contributor.author Lin, Vita Ap en_US
dc.contributor.author Buckle, Andrew en_US
dc.contributor.author Cheong, Kayfong en_US
dc.contributor.author Halani, Nimita en_US
dc.contributor.author Ku, Su en_US
dc.contributor.author Kwok, Chau-To en_US
dc.contributor.author Packham, Deborah en_US
dc.contributor.author Suter, Catherine M. en_US
dc.contributor.author Meagher, Alan en_US
dc.contributor.author Stirzaker, Clare en_US
dc.contributor.author Clark, Susan en_US
dc.contributor.author Hawkins, Nicholas en_US
dc.contributor.author Ward, Robyn L. en_US
dc.date.accessioned 2021-11-25T13:29:55Z
dc.date.available 2021-11-25T13:29:55Z
dc.date.issued 2007 en_US
dc.description.abstract Biallelic promoter methylation and transcriptional silencing of the MLH1 gene occurs in the majority of sporadic colorectal cancers exhibiting microsatellite instability due to defective DNA mismatch repair. Long-range epigenetic silencing of contiguous genes has been found on chromosome 2q14 in colorectal cancer. We hypothesized that epigenetic silencing of MLH1 could occur on a regional scale affecting additional genes within 3p22, rather than as a focal event. We studied the levels of CpG island methylation and expression of multiple contiguous genes across a 4 Mb segment of 3p22 including MLH1 in microsatellite-unstable and -stable cancers, and their paired normal colonic mucosa. We found concordant CpG island hypermethylation, H3-K9 dimethylation and transcriptional silencing of MLH1 and multiple flanking genes spanning up to 2.4 Mb in microsatellite-unstable colorectal cancers. This region was interspersed with unmethylated genes, which were also transcriptionally repressed. Expression of both methylated and unmethylated genes was reactivated by methyltransferase and histone deacetylase inhibitors in a microsatellite-unstable colorectal carcinoma cell line. Two genes at the telomeric end of the region were also hypermethylated in microsatellite-stable cancers, adenomas, and at low levels in normal colonic mucosa from older individuals. Thus, the cluster of genes flanking MLH1 that was specifically methylated in the microsatellite-unstable group of cancers extended across 1.1 Mb. Our results show that coordinate epigenetic silencing extends across a large chromosomal region encompassing MLH1 in microsatellite-unstable colorectal cancers. Simultaneous epigenetic silencing of this cluster of 3p22 genes may contribute to the development or progression of this type of cancer. en_US
dc.identifier.issn 0008-5472 en_US
dc.identifier.uri http://hdl.handle.net/1959.4/39762
dc.language English
dc.language.iso EN en_US
dc.rights CC BY-NC-ND 3.0 en_US
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/3.0/au/ en_US
dc.source Legacy MARC en_US
dc.title Epigenetic inactivation of a cluster of genes flanking MLH1 in microsatellite-unstable colorectal cancer en_US
dc.type Journal Article en
dcterms.accessRights metadata only access
dspace.entity.type Publication en_US
unsw.accessRights.uri http://purl.org/coar/access_right/c_14cb
unsw.identifier.doiPublisher http://dx.doi.org/10.1158/0008-5472.CAN-07-0869 en_US
unsw.relation.faculty Medicine & Health
unsw.relation.ispartofissue 19 en_US
unsw.relation.ispartofjournal Cancer Res en_US
unsw.relation.ispartofpagefrompageto 9107-9116 en_US
unsw.relation.ispartofvolume 67 en_US
unsw.relation.originalPublicationAffiliation Hitchins, Megan P., Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Lin, Vita Ap en_US
unsw.relation.originalPublicationAffiliation Buckle, Andrew, Medical Sciences, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Cheong, Kayfong en_US
unsw.relation.originalPublicationAffiliation Halani, Nimita en_US
unsw.relation.originalPublicationAffiliation Ku, Su en_US
unsw.relation.originalPublicationAffiliation Kwok, Chau-To en_US
unsw.relation.originalPublicationAffiliation Packham, Deborah en_US
unsw.relation.originalPublicationAffiliation Suter, Catherine M., Medical Sciences, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Meagher, Alan, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Stirzaker, Clare en_US
unsw.relation.originalPublicationAffiliation Clark, Susan, Garvan Institute of Medical Research, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Hawkins, Nicholas, Medical Sciences, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Ward, Robyn L., Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW en_US
unsw.relation.school Clinical School St Vincents Hospital *
unsw.relation.school School of Medical Sciences *
unsw.relation.school Garvan Institute *
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