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Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor
Background Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event‐free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatme...
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| Published in: | Pediatric blood & cancer 2012-09, Vol.59 (3), p.499-505 |
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| creator | Ohshima, Junjiro Haruta, Masayuki Fujiwara, Yuiko Watanabe, Naoki Arai, Yasuhito Ariga, Tadashi Okita, Hajime Koshinaga, Tsugumichi Oue, Takaharu Hinotsu, Shiro Nakadate, Hisaya Horie, Hiroshi Fukuzawa, Masahiro Kaneko, Yasuhiko |
| description | Background
Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event‐free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed.
Procedure
We analyzed methylation status of three tumor suppressor genes; Ras‐association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation‐specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors.
Results
RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A‐methylated tumor had shorter overall and event‐free survival periods (P = 0.043 and 0.018, respectively), when a cut‐off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P |
| doi_str_mv | 10.1002/pbc.24093 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1024934653</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1024934653</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3633-ba68d6f95b41320604b0ad1dc82eddfa5369a0c30edab4f3110f006d18ee38f03</originalsourceid><addsrcrecordid>eNp1kMFu1DAURS0EoqWw4AeQl7BI-2zHTrIcRkwBtYAY0CwtJ35hDMk4tR3K_D0u086O1buLc4-eLiEvGZwzAH4xtd05L6ERj8gpk6UsJLDq8TFDc0Kexfgzowpk_ZSccF7KivPqlJhrTNv9YJLzO-p7mrZIvy7W6xVb0Cn40ScM1MWc0bouud94R03eB-rn1PkRqRn97gedsgJ3KdJbl7Z044Yx0jSPPjwnT3ozRHxxf8_I99W7b8v3xdXnyw_LxVXRCSVE0RpVW9U3si2Z4KCgbMFYZruao7W9kUI1BjoBaE1b9oIx6AGUZTWiqHsQZ-T1wZvfvpkxJj262OEwmB36OWoGvGxEqaTI6JsD2gUfY8BeT8GNJuwzpO8W1XlR_W_RzL66187tiPZIPkyYgYsDcOsG3P_fpL-8XT4oi0PDxYR_jg0TfmlViUrqzadLzdX1RqzWtf4o_gJCjI7_</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1024934653</pqid></control><display><type>article</type><title>Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor</title><source>Wiley</source><creator>Ohshima, Junjiro ; Haruta, Masayuki ; Fujiwara, Yuiko ; Watanabe, Naoki ; Arai, Yasuhito ; Ariga, Tadashi ; Okita, Hajime ; Koshinaga, Tsugumichi ; Oue, Takaharu ; Hinotsu, Shiro ; Nakadate, Hisaya ; Horie, Hiroshi ; Fukuzawa, Masahiro ; Kaneko, Yasuhiko</creator><creatorcontrib>Ohshima, Junjiro ; Haruta, Masayuki ; Fujiwara, Yuiko ; Watanabe, Naoki ; Arai, Yasuhito ; Ariga, Tadashi ; Okita, Hajime ; Koshinaga, Tsugumichi ; Oue, Takaharu ; Hinotsu, Shiro ; Nakadate, Hisaya ; Horie, Hiroshi ; Fukuzawa, Masahiro ; Kaneko, Yasuhiko</creatorcontrib><description>Background
Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event‐free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed.
Procedure
We analyzed methylation status of three tumor suppressor genes; Ras‐association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation‐specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors.
Results
RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A‐methylated tumor had shorter overall and event‐free survival periods (P = 0.043 and 0.018, respectively), when a cut‐off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P < 0.001), and in advanced‐stage tumors than early stage tumors (P = 0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P = 0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway.
Conclusions
The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients. Pediatr Blood Cancer 2012;59:499–505. © 2012 Wiley Periodicals, Inc.</description><identifier>ISSN: 1545-5009</identifier><identifier>EISSN: 1545-5017</identifier><identifier>DOI: 10.1002/pbc.24093</identifier><identifier>PMID: 22457227</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>biomarkers ; Biomarkers, Tumor - analysis ; Child ; Disease-Free Survival ; DNA Methylation ; Female ; Humans ; Male ; methylation ; Prognosis ; Promoter Regions, Genetic ; RASSF1A ; Treatment Outcome ; Tumor Suppressor Proteins - genetics ; Wilms tumor ; Wilms Tumor - genetics ; Wilms Tumor - mortality</subject><ispartof>Pediatric blood & cancer, 2012-09, Vol.59 (3), p.499-505</ispartof><rights>Copyright © 2012 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3633-ba68d6f95b41320604b0ad1dc82eddfa5369a0c30edab4f3110f006d18ee38f03</citedby><cites>FETCH-LOGICAL-c3633-ba68d6f95b41320604b0ad1dc82eddfa5369a0c30edab4f3110f006d18ee38f03</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/22457227$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ohshima, Junjiro</creatorcontrib><creatorcontrib>Haruta, Masayuki</creatorcontrib><creatorcontrib>Fujiwara, Yuiko</creatorcontrib><creatorcontrib>Watanabe, Naoki</creatorcontrib><creatorcontrib>Arai, Yasuhito</creatorcontrib><creatorcontrib>Ariga, Tadashi</creatorcontrib><creatorcontrib>Okita, Hajime</creatorcontrib><creatorcontrib>Koshinaga, Tsugumichi</creatorcontrib><creatorcontrib>Oue, Takaharu</creatorcontrib><creatorcontrib>Hinotsu, Shiro</creatorcontrib><creatorcontrib>Nakadate, Hisaya</creatorcontrib><creatorcontrib>Horie, Hiroshi</creatorcontrib><creatorcontrib>Fukuzawa, Masahiro</creatorcontrib><creatorcontrib>Kaneko, Yasuhiko</creatorcontrib><title>Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor</title><title>Pediatric blood & cancer</title><addtitle>Pediatr. Blood Cancer</addtitle><description>Background
Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event‐free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed.
Procedure
We analyzed methylation status of three tumor suppressor genes; Ras‐association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation‐specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors.
Results
RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A‐methylated tumor had shorter overall and event‐free survival periods (P = 0.043 and 0.018, respectively), when a cut‐off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P < 0.001), and in advanced‐stage tumors than early stage tumors (P = 0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P = 0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway.
Conclusions
The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients. Pediatr Blood Cancer 2012;59:499–505. © 2012 Wiley Periodicals, Inc.</description><subject>biomarkers</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Child</subject><subject>Disease-Free Survival</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>methylation</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic</subject><subject>RASSF1A</subject><subject>Treatment Outcome</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Wilms tumor</subject><subject>Wilms Tumor - genetics</subject><subject>Wilms Tumor - mortality</subject><issn>1545-5009</issn><issn>1545-5017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNp1kMFu1DAURS0EoqWw4AeQl7BI-2zHTrIcRkwBtYAY0CwtJ35hDMk4tR3K_D0u086O1buLc4-eLiEvGZwzAH4xtd05L6ERj8gpk6UsJLDq8TFDc0Kexfgzowpk_ZSccF7KivPqlJhrTNv9YJLzO-p7mrZIvy7W6xVb0Cn40ScM1MWc0bouud94R03eB-rn1PkRqRn97gedsgJ3KdJbl7Z044Yx0jSPPjwnT3ozRHxxf8_I99W7b8v3xdXnyw_LxVXRCSVE0RpVW9U3si2Z4KCgbMFYZruao7W9kUI1BjoBaE1b9oIx6AGUZTWiqHsQZ-T1wZvfvpkxJj262OEwmB36OWoGvGxEqaTI6JsD2gUfY8BeT8GNJuwzpO8W1XlR_W_RzL66187tiPZIPkyYgYsDcOsG3P_fpL-8XT4oi0PDxYR_jg0TfmlViUrqzadLzdX1RqzWtf4o_gJCjI7_</recordid><startdate>201209</startdate><enddate>201209</enddate><creator>Ohshima, Junjiro</creator><creator>Haruta, Masayuki</creator><creator>Fujiwara, Yuiko</creator><creator>Watanabe, Naoki</creator><creator>Arai, Yasuhito</creator><creator>Ariga, Tadashi</creator><creator>Okita, Hajime</creator><creator>Koshinaga, Tsugumichi</creator><creator>Oue, Takaharu</creator><creator>Hinotsu, Shiro</creator><creator>Nakadate, Hisaya</creator><creator>Horie, Hiroshi</creator><creator>Fukuzawa, Masahiro</creator><creator>Kaneko, Yasuhiko</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</scope><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>201209</creationdate><title>Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor</title><author>Ohshima, Junjiro ; Haruta, Masayuki ; Fujiwara, Yuiko ; Watanabe, Naoki ; Arai, Yasuhito ; Ariga, Tadashi ; Okita, Hajime ; Koshinaga, Tsugumichi ; Oue, Takaharu ; Hinotsu, Shiro ; Nakadate, Hisaya ; Horie, Hiroshi ; Fukuzawa, Masahiro ; Kaneko, Yasuhiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3633-ba68d6f95b41320604b0ad1dc82eddfa5369a0c30edab4f3110f006d18ee38f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>biomarkers</topic><topic>Biomarkers, Tumor - analysis</topic><topic>Child</topic><topic>Disease-Free Survival</topic><topic>DNA Methylation</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>methylation</topic><topic>Prognosis</topic><topic>Promoter Regions, Genetic</topic><topic>RASSF1A</topic><topic>Treatment Outcome</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Wilms tumor</topic><topic>Wilms Tumor - genetics</topic><topic>Wilms Tumor - mortality</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ohshima, Junjiro</creatorcontrib><creatorcontrib>Haruta, Masayuki</creatorcontrib><creatorcontrib>Fujiwara, Yuiko</creatorcontrib><creatorcontrib>Watanabe, Naoki</creatorcontrib><creatorcontrib>Arai, Yasuhito</creatorcontrib><creatorcontrib>Ariga, Tadashi</creatorcontrib><creatorcontrib>Okita, Hajime</creatorcontrib><creatorcontrib>Koshinaga, Tsugumichi</creatorcontrib><creatorcontrib>Oue, Takaharu</creatorcontrib><creatorcontrib>Hinotsu, Shiro</creatorcontrib><creatorcontrib>Nakadate, Hisaya</creatorcontrib><creatorcontrib>Horie, Hiroshi</creatorcontrib><creatorcontrib>Fukuzawa, Masahiro</creatorcontrib><creatorcontrib>Kaneko, Yasuhiko</creatorcontrib><collection>Istex</collection><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>Pediatric blood & cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ohshima, Junjiro</au><au>Haruta, Masayuki</au><au>Fujiwara, Yuiko</au><au>Watanabe, Naoki</au><au>Arai, Yasuhito</au><au>Ariga, Tadashi</au><au>Okita, Hajime</au><au>Koshinaga, Tsugumichi</au><au>Oue, Takaharu</au><au>Hinotsu, Shiro</au><au>Nakadate, Hisaya</au><au>Horie, Hiroshi</au><au>Fukuzawa, Masahiro</au><au>Kaneko, Yasuhiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor</atitle><jtitle>Pediatric blood & cancer</jtitle><addtitle>Pediatr. Blood Cancer</addtitle><date>2012-09</date><risdate>2012</risdate><volume>59</volume><issue>3</issue><spage>499</spage><epage>505</epage><pages>499-505</pages><issn>1545-5009</issn><eissn>1545-5017</eissn><abstract>Background
Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event‐free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed.
Procedure
We analyzed methylation status of three tumor suppressor genes; Ras‐association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation‐specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors.
Results
RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A‐methylated tumor had shorter overall and event‐free survival periods (P = 0.043 and 0.018, respectively), when a cut‐off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P < 0.001), and in advanced‐stage tumors than early stage tumors (P = 0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P = 0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway.
Conclusions
The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients. Pediatr Blood Cancer 2012;59:499–505. © 2012 Wiley Periodicals, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>22457227</pmid><doi>10.1002/pbc.24093</doi><tpages>7</tpages></addata></record> |
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| subjects | biomarkers Biomarkers, Tumor - analysis Child Disease-Free Survival DNA Methylation Female Humans Male methylation Prognosis Promoter Regions, Genetic RASSF1A Treatment Outcome Tumor Suppressor Proteins - genetics Wilms tumor Wilms Tumor - genetics Wilms Tumor - mortality |
| title | Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor |
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