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Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation
Constitutional epimutation of the DNA mismatch repair gene, MLH1 , represents a minor cause of Lynch syndrome. MLH1 epimutations are characterized by the soma-wide distribution of methylation of a single allele of the MLH1 promoter accompanied by constitutive allelic loss of transcription. ‘Primary’...
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Published in: | Familial cancer 2016-07, Vol.15 (3), p.413-422 |
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description | Constitutional epimutation of the DNA mismatch repair gene,
MLH1
, represents a minor cause of Lynch syndrome.
MLH1
epimutations are characterized by the soma-wide distribution of methylation of a single allele of the
MLH1
promoter accompanied by constitutive allelic loss of transcription. ‘Primary’
MLH1
epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. ‘Secondary’
MLH1
epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of
MLH1
. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for
MLH1
epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting
MLH1
epimutation testing; overlapping molecular pathology features of
MLH1
methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of
MLH1
epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of
MLH1
epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting
MLH1
epimutation testing could provide a cost-effective means of diagnosing these cases. |
doi_str_mv | 10.1007/s10689-016-9887-3 |
format | article |
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MLH1
, represents a minor cause of Lynch syndrome.
MLH1
epimutations are characterized by the soma-wide distribution of methylation of a single allele of the
MLH1
promoter accompanied by constitutive allelic loss of transcription. ‘Primary’
MLH1
epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. ‘Secondary’
MLH1
epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of
MLH1
. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for
MLH1
epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting
MLH1
epimutation testing; overlapping molecular pathology features of
MLH1
methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of
MLH1
epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of
MLH1
epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting
MLH1
epimutation testing could provide a cost-effective means of diagnosing these cases.</description><identifier>ISSN: 1389-9600</identifier><identifier>EISSN: 1573-7292</identifier><identifier>DOI: 10.1007/s10689-016-9887-3</identifier><identifier>PMID: 26886015</identifier><identifier>CODEN: FCAAAJ</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Alleles ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics ; DNA Methylation ; DNA Mismatch Repair ; Early Detection of Cancer - methods ; Epidemiology ; Epigenesis, Genetic ; Genetic Predisposition to Disease ; Genetic Testing - methods ; Germ-Line Mutation ; Human Genetics ; Humans ; Loss of Heterozygosity ; MutL Protein Homolog 1 - genetics ; Original Article ; Practice Guidelines as Topic ; Promoter Regions, Genetic</subject><ispartof>Familial cancer, 2016-07, Vol.15 (3), p.413-422</ispartof><rights>Springer Science+Business Media Dordrecht 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-27edb455656b0b4b0421d307a1e8578861c22cdcf751b3f2a8a15011c240193d3</citedby><cites>FETCH-LOGICAL-c405t-27edb455656b0b4b0421d307a1e8578861c22cdcf751b3f2a8a15011c240193d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26886015$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hitchins, Megan P.</creatorcontrib><title>Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation</title><title>Familial cancer</title><addtitle>Familial Cancer</addtitle><addtitle>Fam Cancer</addtitle><description>Constitutional epimutation of the DNA mismatch repair gene,
MLH1
, represents a minor cause of Lynch syndrome.
MLH1
epimutations are characterized by the soma-wide distribution of methylation of a single allele of the
MLH1
promoter accompanied by constitutive allelic loss of transcription. ‘Primary’
MLH1
epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. ‘Secondary’
MLH1
epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of
MLH1
. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for
MLH1
epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting
MLH1
epimutation testing; overlapping molecular pathology features of
MLH1
methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of
MLH1
epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of
MLH1
epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting
MLH1
epimutation testing could provide a cost-effective means of diagnosing these cases.</description><subject>Alleles</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</subject><subject>DNA Methylation</subject><subject>DNA Mismatch Repair</subject><subject>Early Detection of Cancer - methods</subject><subject>Epidemiology</subject><subject>Epigenesis, Genetic</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Testing - methods</subject><subject>Germ-Line Mutation</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Loss of Heterozygosity</subject><subject>MutL Protein Homolog 1 - genetics</subject><subject>Original Article</subject><subject>Practice Guidelines as Topic</subject><subject>Promoter Regions, Genetic</subject><issn>1389-9600</issn><issn>1573-7292</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNqFkUFv1DAQhS1E1ZbSH8AFWeLSS-iMHccON1TRFmkRFzhbjj3pumycJU6E9t_X2y0IIVWcZjTzvTe2HmNvEN4jgL7MCI1pK8Cmao3RlXzBTlFpWWnRipell2XbNgAn7FXO9wAChNTH7EQ0xjSA6pS565hCTHd8XhNPRGFDPCbu-Nrt8uz8jw88Bkpz7KN3cxwTH3vuXaa8b1a75Nc871KYxoH4rziv-ZfVLXLaxmGZHwWv2VHvNpnOn-oZ-3796dvVbbX6evP56uOq8jWouRKaQlcr1aimg67uoBYYJGiHZJQuz0UvhA--1wo72QtnHCrAMq0BWxnkGbs4-G6n8edCebZDzJ42G5doXLJFA8UEjDT_R3WrTKNQqIK--we9H5cplY88UrVUyuhC4YHy05jzRL3dTnFw084i2H1U9hCVLVHZfVRWFs3bJ-elGyj8UfzOpgDiAOSySnc0_XX6WdcHleScQw</recordid><startdate>20160701</startdate><enddate>20160701</enddate><creator>Hitchins, Megan P.</creator><general>Springer Netherlands</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9-</scope><scope>K9.</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20160701</creationdate><title>Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation</title><author>Hitchins, Megan P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-27edb455656b0b4b0421d307a1e8578861c22cdcf751b3f2a8a15011c240193d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alleles</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</topic><topic>DNA Methylation</topic><topic>DNA Mismatch Repair</topic><topic>Early Detection of Cancer - methods</topic><topic>Epidemiology</topic><topic>Epigenesis, Genetic</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic Testing - methods</topic><topic>Germ-Line Mutation</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Loss of Heterozygosity</topic><topic>MutL Protein Homolog 1 - genetics</topic><topic>Original Article</topic><topic>Practice Guidelines as Topic</topic><topic>Promoter Regions, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hitchins, Megan P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>Consumer Health Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Family Health Database (ProQuest)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Research Library (ProQuest Database)</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Familial cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hitchins, Megan P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation</atitle><jtitle>Familial cancer</jtitle><stitle>Familial Cancer</stitle><addtitle>Fam Cancer</addtitle><date>2016-07-01</date><risdate>2016</risdate><volume>15</volume><issue>3</issue><spage>413</spage><epage>422</epage><pages>413-422</pages><issn>1389-9600</issn><eissn>1573-7292</eissn><coden>FCAAAJ</coden><abstract>Constitutional epimutation of the DNA mismatch repair gene,
MLH1
, represents a minor cause of Lynch syndrome.
MLH1
epimutations are characterized by the soma-wide distribution of methylation of a single allele of the
MLH1
promoter accompanied by constitutive allelic loss of transcription. ‘Primary’
MLH1
epimutations, considered pure epigenetic defects, tend to arise de novo in patients without a family history or any apparent genetic mutation. These demonstrate non-Mendelian inheritance. ‘Secondary’
MLH1
epimutations have a genetic basis and have been linked to non-coding genetic alterations in the vicinity of
MLH1
. These demonstrate autosomal dominant inheritance. Despite convincing evidence of their role in causing Lynch-type cancers, routine screening for
MLH1
epimutations has not been widely adopted. Complicating factors may include: the need to perform additional methylation-based testing beyond the standard genetic screening for a germline mutation; the lack of a consensus algorithm for the selection of patients warranting
MLH1
epimutation testing; overlapping molecular pathology features of
MLH1
methylation and loss of MLH1 expression with more prevalent sporadic MSI cancers; the rarity of
MLH1
epimutation; the variable inter-generational inheritance patterns; and the cost-effectiveness of screening. Nevertheless, a positive molecular diagnosis of
MLH1
epimutation is clinically important because carriers have a high personal risk of developing metachronous Lynch-type cancers, and their relatives may also be at risk of carriage. Extending existing universal and clinic-based screening algorithms for Lynch syndrome to include an additional arm of selection criteria for cases warranting
MLH1
epimutation testing could provide a cost-effective means of diagnosing these cases.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>26886015</pmid><doi>10.1007/s10689-016-9887-3</doi><tpages>10</tpages></addata></record> |
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subjects | Alleles Biomedical and Life Sciences Biomedicine Cancer Research Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis Colorectal Neoplasms, Hereditary Nonpolyposis - genetics DNA Methylation DNA Mismatch Repair Early Detection of Cancer - methods Epidemiology Epigenesis, Genetic Genetic Predisposition to Disease Genetic Testing - methods Germ-Line Mutation Human Genetics Humans Loss of Heterozygosity MutL Protein Homolog 1 - genetics Original Article Practice Guidelines as Topic Promoter Regions, Genetic |
title | Finding the needle in a haystack: identification of cases of Lynch syndrome with MLH1 epimutation |
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