MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis
(1) Background: hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly, hypermethylation is considered a somatic and sporadic event in cancer, and it...
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| Veröffentlicht in: | Genes 2023-11, Vol.14 (11), p.2060 |
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| description | (1) Background:
hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly,
hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However,
hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of
protein expression and microsatellite instability. All cases were investigated for
promoter methylation and
germline variants. (3) Results: Somatic
promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of
germline pathogenic variants. In two families, primary and secondary
epimutations were demonstrated. (4) Conclusions:
hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are
hypermethylated. Current flow charts for universal LS screening, which include
methylation, should be applied, paying attention to a patient's family and personal history. |
| doi_str_mv | 10.3390/genes14112060 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2893844044</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2893844044</sourcerecordid><originalsourceid>FETCH-LOGICAL-c360t-42c796a4b3fa8004431f43af7e013ffe222d82763d22fb844d5793d5c5d78b433</originalsourceid><addsrcrecordid>eNpdkEtLw0AUhQdRbKldupUBN26i88prqUWtkKJYXYdJ5o5NSWbqTLLIvzd9KOrlwr2L7xwOB6FzSq45T8nNBxjwVFDKSESO0JiRmAdCsPD41z9CU-_XZBhBGCHhKRrxhBA-7Bi9LrI5xS_ONrYFhxfQrvpatpU1eGa7WuE7wO0K8BJKaxSeVy2uDM56U67wsjdqEAKeSVdWxu7SVP4MnWhZe5ge7gS9P9y_zeZB9vz4NLvNgpJHpA0EK-M0kqLgWg5xhOBUCy51DIRyrYExphIWR1wxpotECBXGKVdhGao4KQTnE3S19904-9mBb_Om8iXUtTRgO5-zJOWDbOs8QZf_0LXtnBnS7SgiIkq3VLCnSme9d6Dzjasa6fqcknzbd_6n74G_OLh2RQPqh_5ul38By694yg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2893046114</pqid></control><display><type>article</type><title>MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis</title><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>PubMed Central Open Access</source><creator>Carnevali, Ileana Wanda ; Cini, Giulia ; Libera, Laura ; Sahnane, Nora ; Facchi, Sofia ; Viel, Alessandra ; Sessa, Fausto ; Tibiletti, Maria Grazia</creator><creatorcontrib>Carnevali, Ileana Wanda ; Cini, Giulia ; Libera, Laura ; Sahnane, Nora ; Facchi, Sofia ; Viel, Alessandra ; Sessa, Fausto ; Tibiletti, Maria Grazia</creatorcontrib><description>(1) Background:
hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly,
hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However,
hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of
protein expression and microsatellite instability. All cases were investigated for
promoter methylation and
germline variants. (3) Results: Somatic
promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of
germline pathogenic variants. In two families, primary and secondary
epimutations were demonstrated. (4) Conclusions:
hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are
hypermethylated. Current flow charts for universal LS screening, which include
methylation, should be applied, paying attention to a patient's family and personal history.</description><identifier>ISSN: 2073-4425</identifier><identifier>EISSN: 2073-4425</identifier><identifier>DOI: 10.3390/genes14112060</identifier><identifier>PMID: 38003003</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Carcinogenesis ; Carcinogenesis - genetics ; Colorectal carcinoma ; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis - pathology ; DNA methylation ; DNA Methylation - genetics ; Endometrial cancer ; Endometrial Neoplasms - diagnosis ; Endometrium ; Epigenetics ; Female ; Gastric cancer ; Gene silencing ; Genetic counseling ; Genetic Predisposition to Disease ; Genetic testing ; Humans ; Microsatellite Instability ; MLH1 protein ; Mutation ; MutL Protein Homolog 1 - genetics ; Ovarian cancer ; Software ; Tumorigenesis</subject><ispartof>Genes, 2023-11, Vol.14 (11), p.2060</ispartof><rights>2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c360t-42c796a4b3fa8004431f43af7e013ffe222d82763d22fb844d5793d5c5d78b433</citedby><cites>FETCH-LOGICAL-c360t-42c796a4b3fa8004431f43af7e013ffe222d82763d22fb844d5793d5c5d78b433</cites><orcidid>0000-0003-2130-6669 ; 0000-0002-0511-5427 ; 0000-0003-2804-0840</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38003003$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carnevali, Ileana Wanda</creatorcontrib><creatorcontrib>Cini, Giulia</creatorcontrib><creatorcontrib>Libera, Laura</creatorcontrib><creatorcontrib>Sahnane, Nora</creatorcontrib><creatorcontrib>Facchi, Sofia</creatorcontrib><creatorcontrib>Viel, Alessandra</creatorcontrib><creatorcontrib>Sessa, Fausto</creatorcontrib><creatorcontrib>Tibiletti, Maria Grazia</creatorcontrib><title>MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis</title><title>Genes</title><addtitle>Genes (Basel)</addtitle><description>(1) Background:
hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly,
hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However,
hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of
protein expression and microsatellite instability. All cases were investigated for
promoter methylation and
germline variants. (3) Results: Somatic
promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of
germline pathogenic variants. In two families, primary and secondary
epimutations were demonstrated. (4) Conclusions:
hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are
hypermethylated. Current flow charts for universal LS screening, which include
methylation, should be applied, paying attention to a patient's family and personal history.</description><subject>Carcinogenesis</subject><subject>Carcinogenesis - genetics</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - pathology</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - diagnosis</subject><subject>Endometrium</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Gastric cancer</subject><subject>Gene silencing</subject><subject>Genetic counseling</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic testing</subject><subject>Humans</subject><subject>Microsatellite Instability</subject><subject>MLH1 protein</subject><subject>Mutation</subject><subject>MutL Protein Homolog 1 - genetics</subject><subject>Ovarian cancer</subject><subject>Software</subject><subject>Tumorigenesis</subject><issn>2073-4425</issn><issn>2073-4425</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkEtLw0AUhQdRbKldupUBN26i88prqUWtkKJYXYdJ5o5NSWbqTLLIvzd9KOrlwr2L7xwOB6FzSq45T8nNBxjwVFDKSESO0JiRmAdCsPD41z9CU-_XZBhBGCHhKRrxhBA-7Bi9LrI5xS_ONrYFhxfQrvpatpU1eGa7WuE7wO0K8BJKaxSeVy2uDM56U67wsjdqEAKeSVdWxu7SVP4MnWhZe5ge7gS9P9y_zeZB9vz4NLvNgpJHpA0EK-M0kqLgWg5xhOBUCy51DIRyrYExphIWR1wxpotECBXGKVdhGao4KQTnE3S19904-9mBb_Om8iXUtTRgO5-zJOWDbOs8QZf_0LXtnBnS7SgiIkq3VLCnSme9d6Dzjasa6fqcknzbd_6n74G_OLh2RQPqh_5ul38By694yg</recordid><startdate>20231109</startdate><enddate>20231109</enddate><creator>Carnevali, Ileana Wanda</creator><creator>Cini, Giulia</creator><creator>Libera, Laura</creator><creator>Sahnane, Nora</creator><creator>Facchi, Sofia</creator><creator>Viel, Alessandra</creator><creator>Sessa, Fausto</creator><creator>Tibiletti, Maria Grazia</creator><general>MDPI AG</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>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2130-6669</orcidid><orcidid>https://orcid.org/0000-0002-0511-5427</orcidid><orcidid>https://orcid.org/0000-0003-2804-0840</orcidid></search><sort><creationdate>20231109</creationdate><title>MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis</title><author>Carnevali, Ileana Wanda ; Cini, Giulia ; Libera, Laura ; Sahnane, Nora ; Facchi, Sofia ; Viel, Alessandra ; Sessa, Fausto ; Tibiletti, Maria Grazia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c360t-42c796a4b3fa8004431f43af7e013ffe222d82763d22fb844d5793d5c5d78b433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Carcinogenesis</topic><topic>Carcinogenesis - genetics</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - pathology</topic><topic>DNA methylation</topic><topic>DNA Methylation - genetics</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - diagnosis</topic><topic>Endometrium</topic><topic>Epigenetics</topic><topic>Female</topic><topic>Gastric cancer</topic><topic>Gene silencing</topic><topic>Genetic counseling</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic testing</topic><topic>Humans</topic><topic>Microsatellite Instability</topic><topic>MLH1 protein</topic><topic>Mutation</topic><topic>MutL Protein Homolog 1 - genetics</topic><topic>Ovarian cancer</topic><topic>Software</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carnevali, Ileana Wanda</creatorcontrib><creatorcontrib>Cini, Giulia</creatorcontrib><creatorcontrib>Libera, Laura</creatorcontrib><creatorcontrib>Sahnane, Nora</creatorcontrib><creatorcontrib>Facchi, Sofia</creatorcontrib><creatorcontrib>Viel, Alessandra</creatorcontrib><creatorcontrib>Sessa, Fausto</creatorcontrib><creatorcontrib>Tibiletti, Maria Grazia</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</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>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Genes</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carnevali, Ileana Wanda</au><au>Cini, Giulia</au><au>Libera, Laura</au><au>Sahnane, Nora</au><au>Facchi, Sofia</au><au>Viel, Alessandra</au><au>Sessa, Fausto</au><au>Tibiletti, Maria Grazia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis</atitle><jtitle>Genes</jtitle><addtitle>Genes (Basel)</addtitle><date>2023-11-09</date><risdate>2023</risdate><volume>14</volume><issue>11</issue><spage>2060</spage><pages>2060-</pages><issn>2073-4425</issn><eissn>2073-4425</eissn><abstract>(1) Background:
hypermethylation is an epigenetic alteration in the tumorigenesis of colorectal cancer (CRC) and endometrial cancer (EC), causing gene silencing, and, as a consequence, microsatellite instability. Commonly,
hypermethylation is considered a somatic and sporadic event in cancer, and its detection is recognized as a useful tool to distinguish sporadic from inherited conditions (such as, Lynch syndrome (LS)). However,
hypermethylation has been described in rare cases of CRC and EC in LS patients. (2) Methods: A total of 61 cancers (31 CRCs, 27 ECs, 2 ovarian cancers, and 1 stomach cancer) from 56 patients referred to cancer genetic counselling were selected for loss of
protein expression and microsatellite instability. All cases were investigated for
promoter methylation and
germline variants. (3) Results: Somatic
promoter hypermethylation was identified in 16.7% of CRC and in 40% of EC carriers of
germline pathogenic variants. In two families, primary and secondary
epimutations were demonstrated. (4) Conclusions:
hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are
hypermethylated. Current flow charts for universal LS screening, which include
methylation, should be applied, paying attention to a patient's family and personal history.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>38003003</pmid><doi>10.3390/genes14112060</doi><orcidid>https://orcid.org/0000-0003-2130-6669</orcidid><orcidid>https://orcid.org/0000-0002-0511-5427</orcidid><orcidid>https://orcid.org/0000-0003-2804-0840</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Carcinogenesis Carcinogenesis - genetics Colorectal carcinoma Colorectal Neoplasms, Hereditary Nonpolyposis - genetics Colorectal Neoplasms, Hereditary Nonpolyposis - pathology DNA methylation DNA Methylation - genetics Endometrial cancer Endometrial Neoplasms - diagnosis Endometrium Epigenetics Female Gastric cancer Gene silencing Genetic counseling Genetic Predisposition to Disease Genetic testing Humans Microsatellite Instability MLH1 protein Mutation MutL Protein Homolog 1 - genetics Ovarian cancer Software Tumorigenesis |
| title | MLH1 Promoter Methylation Could Be the Second Hit in Lynch Syndrome Carcinogenesis |
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