MLH1 region polymorphisms show a significant association with CpG island shore methylation in a large cohort of healthy individuals
Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instabili...
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| description | Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instability (MSI) in colorectal cancer (CRC) patients. Recent studies have identified less CpG-dense "shore" regions flanking many CpG islands. These shores often exhibit distinct methylation profiles between different tissues and matched normal versus tumor cells of patients. To date, most epigenetic studies have focused on somatic methylation events occurring within solid tumors; less is known of the contributions of peripheral blood cell (PBC) methylation to processes such as aging and tumorigenesis. To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada. Analysis of a region of chromosome 3p21 spanning the MLH1 locus in healthy controls revealed that a CpG island shore 1 kb upstream of the MLH1 gene exhibits different methylation profiles when stratified by SNP genotypes (rs1800734, rs749072, and rs13098279). Individuals with wild-type genotypes incur significantly higher PBC shore methylation than heterozygous or homozygous variant carriers (p |
| doi_str_mv | 10.1371/journal.pone.0051531 |
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We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instability (MSI) in colorectal cancer (CRC) patients. Recent studies have identified less CpG-dense "shore" regions flanking many CpG islands. These shores often exhibit distinct methylation profiles between different tissues and matched normal versus tumor cells of patients. To date, most epigenetic studies have focused on somatic methylation events occurring within solid tumors; less is known of the contributions of peripheral blood cell (PBC) methylation to processes such as aging and tumorigenesis. To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada. Analysis of a region of chromosome 3p21 spanning the MLH1 locus in healthy controls revealed that a CpG island shore 1 kb upstream of the MLH1 gene exhibits different methylation profiles when stratified by SNP genotypes (rs1800734, rs749072, and rs13098279). Individuals with wild-type genotypes incur significantly higher PBC shore methylation than heterozygous or homozygous variant carriers (p<1.1×10(-6); ANOVA). This trend is also seen in CRC cases (p<0.096; ANOVA). Shore methylation also decreases significantly with increasing age in cases and controls. This is the first study of its kind to integrate PBC methylation at a CpG island shore with SNP genotype status in CRC cases and controls. These results indicate that CpG island shore methylation in PBCs may be influenced by genotype as well as the normal aging process.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0051531</identifier><identifier>PMID: 23240038</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptor Proteins, Signal Transducing - blood ; Adaptor Proteins, Signal Transducing - genetics ; Age ; Aged ; Aging ; Analysis ; Biology ; Blood Cells ; Cancer research ; Cell Transformation, Neoplastic ; Chromosome 3 ; Chromosomes ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - blood ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; CpG islands ; CpG Islands - genetics ; Deoxyribonucleic acid ; Disease ; DNA ; DNA methylation ; DNA Methylation - genetics ; DNA microarrays ; Epigenetic inheritance ; Epigenetics ; Female ; Gene expression ; Genes ; Genetic aspects ; Genetic Association Studies ; Genetic diversity ; Genomes ; Genotype ; Genotypes ; Haplotypes ; Humans ; Laboratories ; Male ; Medical research ; Medicine ; Methylation ; Microsatellite instability ; Middle Aged ; MLH1 protein ; MutL Protein Homolog 1 ; Nuclear Proteins - blood ; Nuclear Proteins - genetics ; Oligonucleotide Array Sequence Analysis ; Patients ; Peripheral blood ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Prostate ; Shores ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Solid tumors ; Stability ; Studies ; Tissues ; Tumor cells ; Tumorigenesis ; Tumors ; Variance analysis</subject><ispartof>PloS one, 2012-12, Vol.7 (12), p.e51531</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Savio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Savio et al 2012 Savio et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-adfdb303ba447fc8e942974639222c687e86394528343f6bdfd0d1342cd4fa2e3</citedby><cites>FETCH-LOGICAL-c692t-adfdb303ba447fc8e942974639222c687e86394528343f6bdfd0d1342cd4fa2e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519863/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519863/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2101,2927,23865,27923,27924,53790,53792,79471,79472</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23240038$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Coleman, William B.</contributor><creatorcontrib>Savio, Andrea J</creatorcontrib><creatorcontrib>Lemire, Mathieu</creatorcontrib><creatorcontrib>Mrkonjic, Miralem</creatorcontrib><creatorcontrib>Gallinger, Steven</creatorcontrib><creatorcontrib>Zanke, Brent W</creatorcontrib><creatorcontrib>Hudson, Thomas J</creatorcontrib><creatorcontrib>Bapat, Bharati</creatorcontrib><title>MLH1 region polymorphisms show a significant association with CpG island shore methylation in a large cohort of healthy individuals</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instability (MSI) in colorectal cancer (CRC) patients. Recent studies have identified less CpG-dense "shore" regions flanking many CpG islands. These shores often exhibit distinct methylation profiles between different tissues and matched normal versus tumor cells of patients. To date, most epigenetic studies have focused on somatic methylation events occurring within solid tumors; less is known of the contributions of peripheral blood cell (PBC) methylation to processes such as aging and tumorigenesis. To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada. Analysis of a region of chromosome 3p21 spanning the MLH1 locus in healthy controls revealed that a CpG island shore 1 kb upstream of the MLH1 gene exhibits different methylation profiles when stratified by SNP genotypes (rs1800734, rs749072, and rs13098279). Individuals with wild-type genotypes incur significantly higher PBC shore methylation than heterozygous or homozygous variant carriers (p<1.1×10(-6); ANOVA). This trend is also seen in CRC cases (p<0.096; ANOVA). Shore methylation also decreases significantly with increasing age in cases and controls. This is the first study of its kind to integrate PBC methylation at a CpG island shore with SNP genotype status in CRC cases and controls. These results indicate that CpG island shore methylation in PBCs may be influenced by genotype as well as the normal aging process.</description><subject>Adaptor Proteins, Signal Transducing - blood</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Age</subject><subject>Aged</subject><subject>Aging</subject><subject>Analysis</subject><subject>Biology</subject><subject>Blood Cells</subject><subject>Cancer research</subject><subject>Cell Transformation, Neoplastic</subject><subject>Chromosome 3</subject><subject>Chromosomes</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - blood</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>CpG islands</subject><subject>CpG Islands - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>Disease</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>DNA microarrays</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Association Studies</subject><subject>Genetic diversity</subject><subject>Genomes</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Laboratories</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Methylation</subject><subject>Microsatellite instability</subject><subject>Middle Aged</subject><subject>MLH1 protein</subject><subject>MutL Protein Homolog 1</subject><subject>Nuclear Proteins - blood</subject><subject>Nuclear Proteins - genetics</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Promoter Regions, Genetic</subject><subject>Prostate</subject><subject>Shores</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>Solid tumors</subject><subject>Stability</subject><subject>Studies</subject><subject>Tissues</subject><subject>Tumor cells</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Variance 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region polymorphisms show a significant association with CpG island shore methylation in a large cohort of healthy individuals</title><author>Savio, Andrea J ; Lemire, Mathieu ; Mrkonjic, Miralem ; Gallinger, Steven ; Zanke, Brent W ; Hudson, Thomas J ; Bapat, Bharati</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-adfdb303ba447fc8e942974639222c687e86394528343f6bdfd0d1342cd4fa2e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptor Proteins, Signal Transducing - blood</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Age</topic><topic>Aged</topic><topic>Aging</topic><topic>Analysis</topic><topic>Biology</topic><topic>Blood Cells</topic><topic>Cancer research</topic><topic>Cell Transformation, Neoplastic</topic><topic>Chromosome 3</topic><topic>Chromosomes</topic><topic>Colorectal cancer</topic><topic>Colorectal 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Brent W</au><au>Hudson, Thomas J</au><au>Bapat, Bharati</au><au>Coleman, William B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MLH1 region polymorphisms show a significant association with CpG island shore methylation in a large cohort of healthy individuals</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-12-11</date><risdate>2012</risdate><volume>7</volume><issue>12</issue><spage>e51531</spage><pages>e51531-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instability (MSI) in colorectal cancer (CRC) patients. Recent studies have identified less CpG-dense "shore" regions flanking many CpG islands. These shores often exhibit distinct methylation profiles between different tissues and matched normal versus tumor cells of patients. To date, most epigenetic studies have focused on somatic methylation events occurring within solid tumors; less is known of the contributions of peripheral blood cell (PBC) methylation to processes such as aging and tumorigenesis. To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada. Analysis of a region of chromosome 3p21 spanning the MLH1 locus in healthy controls revealed that a CpG island shore 1 kb upstream of the MLH1 gene exhibits different methylation profiles when stratified by SNP genotypes (rs1800734, rs749072, and rs13098279). Individuals with wild-type genotypes incur significantly higher PBC shore methylation than heterozygous or homozygous variant carriers (p<1.1×10(-6); ANOVA). This trend is also seen in CRC cases (p<0.096; ANOVA). Shore methylation also decreases significantly with increasing age in cases and controls. This is the first study of its kind to integrate PBC methylation at a CpG island shore with SNP genotype status in CRC cases and controls. These results indicate that CpG island shore methylation in PBCs may be influenced by genotype as well as the normal aging process.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23240038</pmid><doi>10.1371/journal.pone.0051531</doi><tpages>e51531</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1327136277 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adaptor Proteins, Signal Transducing - blood Adaptor Proteins, Signal Transducing - genetics Age Aged Aging Analysis Biology Blood Cells Cancer research Cell Transformation, Neoplastic Chromosome 3 Chromosomes Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - blood Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology CpG islands CpG Islands - genetics Deoxyribonucleic acid Disease DNA DNA methylation DNA Methylation - genetics DNA microarrays Epigenetic inheritance Epigenetics Female Gene expression Genes Genetic aspects Genetic Association Studies Genetic diversity Genomes Genotype Genotypes Haplotypes Humans Laboratories Male Medical research Medicine Methylation Microsatellite instability Middle Aged MLH1 protein MutL Protein Homolog 1 Nuclear Proteins - blood Nuclear Proteins - genetics Oligonucleotide Array Sequence Analysis Patients Peripheral blood Polymorphism, Single Nucleotide Promoter Regions, Genetic Prostate Shores Single nucleotide polymorphisms Single-nucleotide polymorphism Solid tumors Stability Studies Tissues Tumor cells Tumorigenesis Tumors Variance analysis |
| title | MLH1 region polymorphisms show a significant association with CpG island shore methylation in a large cohort of healthy individuals |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T13%3A36%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MLH1%20region%20polymorphisms%20show%20a%20significant%20association%20with%20CpG%20island%20shore%20methylation%20in%20a%20large%20cohort%20of%20healthy%20individuals&rft.jtitle=PloS%20one&rft.au=Savio,%20Andrea%20J&rft.date=2012-12-11&rft.volume=7&rft.issue=12&rft.spage=e51531&rft.pages=e51531-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0051531&rft_dat=%3Cgale_plos_%3EA477083918%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1327136277&rft_id=info:pmid/23240038&rft_galeid=A477083918&rft_doaj_id=oai_doaj_org_article_8e725420345640c7b0fbda0d37af9325&rfr_iscdi=true |