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Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia
By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplifica...
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| Published in: | Leukemia & lymphoma 2008-01, Vol.49 (6), p.1132-1141 |
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| container_title | Leukemia & lymphoma |
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| creator | Hess, Corine J. Errami, Abdellatif Berkhof, Johannes Denkers, Fedor Ossenkoppele, Gert J. Nygren, Anders O. H. Schuurhuis, Gerrit J. Waisfisz, Quinten |
| description | By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplification (MS-MLPA) revealed methylation of at least one TSG in 59 119 patients, while no methylation was found in controls. Methylation of different TSGs within patients was substantially correlated (intra-class correlation; 0.38). ESR1 methylation (34 119) strongly predicted concurrent methylation of other genes, OR 7.33 (95%CI 4.13-12.99). A Cox regression model that included the three most frequently methylated TSGs ESR1, CDKN2B p15 and IGSF4, showed ESR1 to have opposite effects on overall survival (OS) compared with the other two, HR 0.22 (95% CI 0.09-0.53) and HR 1.66 (95% CI 0.73-3.79), HR 1.61 (95%CI 0.66-3.93). By assessment of CDKN2B p15 and IGSF4 methylation, patients with methylation at multiple loci can be identified. Accumulation of methylation aberrancies is much more pronounced in ESR1 methylated patients. When combined, the methylation status of ESR1, CDKN2B p15 and IGSF4 enable identification of patient subgroups with large differences in OS (p |
| doi_str_mv | 10.1080/10428190802035990 |
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H. ; Schuurhuis, Gerrit J. ; Waisfisz, Quinten</creator><creatorcontrib>Hess, Corine J. ; Errami, Abdellatif ; Berkhof, Johannes ; Denkers, Fedor ; Ossenkoppele, Gert J. ; Nygren, Anders O. H. ; Schuurhuis, Gerrit J. ; Waisfisz, Quinten</creatorcontrib><description>By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplification (MS-MLPA) revealed methylation of at least one TSG in 59 119 patients, while no methylation was found in controls. Methylation of different TSGs within patients was substantially correlated (intra-class correlation; 0.38). ESR1 methylation (34 119) strongly predicted concurrent methylation of other genes, OR 7.33 (95%CI 4.13-12.99). A Cox regression model that included the three most frequently methylated TSGs ESR1, CDKN2B p15 and IGSF4, showed ESR1 to have opposite effects on overall survival (OS) compared with the other two, HR 0.22 (95% CI 0.09-0.53) and HR 1.66 (95% CI 0.73-3.79), HR 1.61 (95%CI 0.66-3.93). By assessment of CDKN2B p15 and IGSF4 methylation, patients with methylation at multiple loci can be identified. Accumulation of methylation aberrancies is much more pronounced in ESR1 methylated patients. When combined, the methylation status of ESR1, CDKN2B p15 and IGSF4 enable identification of patient subgroups with large differences in OS (p <0.0001). This study shows that methylation profiling allows risk stratification in AML. In addition, ESR1 methylation may reflect a biological pathway that leads to hypermethylation of multiple genes, which is reflected by methylation of IGSF4 and or CDKN2B p15.</description><identifier>ISSN: 1042-8194</identifier><identifier>EISSN: 1029-2403</identifier><identifier>DOI: 10.1080/10428190802035990</identifier><identifier>PMID: 18569637</identifier><language>eng</language><publisher>United States: Informa UK Ltd</publisher><subject>acute myeloid leukemia ; Adolescent ; Adult ; Aged ; Case-Control Studies ; DNA - genetics ; DNA Methylation ; DNA methylation/epigenetics ; Estrogen Receptor alpha - genetics ; Female ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Myeloid, Acute - classification ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - pathology ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prognosis ; Promoter Regions, Genetic - genetics ; Risk assessment ; Survival Rate ; tumor suppressor genes ; Tumor Suppressor Proteins - genetics</subject><ispartof>Leukemia & lymphoma, 2008-01, Vol.49 (6), p.1132-1141</ispartof><rights>2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-d5d004c097d7d50bd00653d077341938392dd73d732446e22d4064948de6ec33</citedby><cites>FETCH-LOGICAL-c404t-d5d004c097d7d50bd00653d077341938392dd73d732446e22d4064948de6ec33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18569637$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hess, Corine J.</creatorcontrib><creatorcontrib>Errami, Abdellatif</creatorcontrib><creatorcontrib>Berkhof, Johannes</creatorcontrib><creatorcontrib>Denkers, Fedor</creatorcontrib><creatorcontrib>Ossenkoppele, Gert J.</creatorcontrib><creatorcontrib>Nygren, Anders O. H.</creatorcontrib><creatorcontrib>Schuurhuis, Gerrit J.</creatorcontrib><creatorcontrib>Waisfisz, Quinten</creatorcontrib><title>Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia</title><title>Leukemia & lymphoma</title><addtitle>Leuk Lymphoma</addtitle><description>By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplification (MS-MLPA) revealed methylation of at least one TSG in 59 119 patients, while no methylation was found in controls. Methylation of different TSGs within patients was substantially correlated (intra-class correlation; 0.38). ESR1 methylation (34 119) strongly predicted concurrent methylation of other genes, OR 7.33 (95%CI 4.13-12.99). A Cox regression model that included the three most frequently methylated TSGs ESR1, CDKN2B p15 and IGSF4, showed ESR1 to have opposite effects on overall survival (OS) compared with the other two, HR 0.22 (95% CI 0.09-0.53) and HR 1.66 (95% CI 0.73-3.79), HR 1.61 (95%CI 0.66-3.93). By assessment of CDKN2B p15 and IGSF4 methylation, patients with methylation at multiple loci can be identified. Accumulation of methylation aberrancies is much more pronounced in ESR1 methylated patients. When combined, the methylation status of ESR1, CDKN2B p15 and IGSF4 enable identification of patient subgroups with large differences in OS (p <0.0001). This study shows that methylation profiling allows risk stratification in AML. In addition, ESR1 methylation may reflect a biological pathway that leads to hypermethylation of multiple genes, which is reflected by methylation of IGSF4 and or CDKN2B p15.</description><subject>acute myeloid leukemia</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Case-Control Studies</subject><subject>DNA - genetics</subject><subject>DNA Methylation</subject><subject>DNA methylation/epigenetics</subject><subject>Estrogen Receptor alpha - genetics</subject><subject>Female</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - classification</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Polymerase Chain Reaction</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Risk assessment</subject><subject>Survival Rate</subject><subject>tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - genetics</subject><issn>1042-8194</issn><issn>1029-2403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNp9kEuLVDEQhYMozjj6A9xIVu6uVh73EXQjjS8YcDP7Syapa6fNY8wD6X8_GbpBRBgoqFPwnUNxCHnN4B2DBd4zkHxhqksOYlQKnpBLBlwNXIJ4-qAlHzogL8iLUg4AMKqJPycXbBknNYn5khx2KZqWM8ZKA9b90evqUqRpo3c5hVQxF7p1RWsLKVNdSjJOV7T0J0YsnULrTC00tWpSQOoi1aZVpOGIPjlLPbZfGJx-SZ5t2hd8dd5X5ObL55vdt-H6x9fvu0_Xg5Eg62BHCyANqNnOdoTbfk2jsDDPQjIlFqG4tbPow6WckHMrYZJKLhYnNEJckben2P7_74alrsEVg97riKmVdVJcciZ5B9kJNDmVknFb77ILOh9XButDv-t__XbPm3N4uw1o_zrOhXbg4wlwcUs56D8pe7tWffQpb1lH48oqHsv_8I99j9rXvdEZ10NqOfbeHvnuHklFm80</recordid><startdate>20080101</startdate><enddate>20080101</enddate><creator>Hess, Corine J.</creator><creator>Errami, Abdellatif</creator><creator>Berkhof, Johannes</creator><creator>Denkers, Fedor</creator><creator>Ossenkoppele, Gert J.</creator><creator>Nygren, Anders O. H.</creator><creator>Schuurhuis, Gerrit J.</creator><creator>Waisfisz, Quinten</creator><general>Informa UK Ltd</general><general>Taylor & Francis</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>7X8</scope></search><sort><creationdate>20080101</creationdate><title>Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia</title><author>Hess, Corine J. ; Errami, Abdellatif ; Berkhof, Johannes ; Denkers, Fedor ; Ossenkoppele, Gert J. ; Nygren, Anders O. H. ; Schuurhuis, Gerrit J. ; Waisfisz, Quinten</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-d5d004c097d7d50bd00653d077341938392dd73d732446e22d4064948de6ec33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>acute myeloid leukemia</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Case-Control Studies</topic><topic>DNA - genetics</topic><topic>DNA Methylation</topic><topic>DNA methylation/epigenetics</topic><topic>Estrogen Receptor alpha - genetics</topic><topic>Female</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - classification</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Polymerase Chain Reaction</topic><topic>Prognosis</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Risk assessment</topic><topic>Survival Rate</topic><topic>tumor suppressor genes</topic><topic>Tumor Suppressor Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hess, Corine J.</creatorcontrib><creatorcontrib>Errami, Abdellatif</creatorcontrib><creatorcontrib>Berkhof, Johannes</creatorcontrib><creatorcontrib>Denkers, Fedor</creatorcontrib><creatorcontrib>Ossenkoppele, Gert J.</creatorcontrib><creatorcontrib>Nygren, Anders O. H.</creatorcontrib><creatorcontrib>Schuurhuis, Gerrit J.</creatorcontrib><creatorcontrib>Waisfisz, Quinten</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Leukemia & lymphoma</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hess, Corine J.</au><au>Errami, Abdellatif</au><au>Berkhof, Johannes</au><au>Denkers, Fedor</au><au>Ossenkoppele, Gert J.</au><au>Nygren, Anders O. H.</au><au>Schuurhuis, Gerrit J.</au><au>Waisfisz, Quinten</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia</atitle><jtitle>Leukemia & lymphoma</jtitle><addtitle>Leuk Lymphoma</addtitle><date>2008-01-01</date><risdate>2008</risdate><volume>49</volume><issue>6</issue><spage>1132</spage><epage>1141</epage><pages>1132-1141</pages><issn>1042-8194</issn><eissn>1029-2403</eissn><abstract>By assessment of the methylation status of 25 candidate tumor suppressor genes (TSGs) in 119 acute myeloid leukemia (AML) patients and 5 controls, we aimed to determine whether simultaneous methylation of multiple TSGs exerts prognostic impact. Methylation-specific multiplex ligation probe amplification (MS-MLPA) revealed methylation of at least one TSG in 59 119 patients, while no methylation was found in controls. Methylation of different TSGs within patients was substantially correlated (intra-class correlation; 0.38). ESR1 methylation (34 119) strongly predicted concurrent methylation of other genes, OR 7.33 (95%CI 4.13-12.99). A Cox regression model that included the three most frequently methylated TSGs ESR1, CDKN2B p15 and IGSF4, showed ESR1 to have opposite effects on overall survival (OS) compared with the other two, HR 0.22 (95% CI 0.09-0.53) and HR 1.66 (95% CI 0.73-3.79), HR 1.61 (95%CI 0.66-3.93). By assessment of CDKN2B p15 and IGSF4 methylation, patients with methylation at multiple loci can be identified. Accumulation of methylation aberrancies is much more pronounced in ESR1 methylated patients. When combined, the methylation status of ESR1, CDKN2B p15 and IGSF4 enable identification of patient subgroups with large differences in OS (p <0.0001). This study shows that methylation profiling allows risk stratification in AML. In addition, ESR1 methylation may reflect a biological pathway that leads to hypermethylation of multiple genes, which is reflected by methylation of IGSF4 and or CDKN2B p15.</abstract><cop>United States</cop><pub>Informa UK Ltd</pub><pmid>18569637</pmid><doi>10.1080/10428190802035990</doi><tpages>10</tpages></addata></record> |
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| subjects | acute myeloid leukemia Adolescent Adult Aged Case-Control Studies DNA - genetics DNA Methylation DNA methylation/epigenetics Estrogen Receptor alpha - genetics Female Gene Expression Regulation, Leukemic Humans Leukemia, Myeloid, Acute - classification Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - pathology Male Middle Aged Polymerase Chain Reaction Prognosis Promoter Regions, Genetic - genetics Risk assessment Survival Rate tumor suppressor genes Tumor Suppressor Proteins - genetics |
| title | Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia |
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