Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study
The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patien...
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| Veröffentlicht in: | Blood 2008-10, Vol.112 (8), p.3088-3098 |
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| creator | Young, Ken H. Leroy, Karen Møller, Michael B. Colleoni, Gisele W.B. Sánchez-Beato, Margarita Kerbauy, Fábio R. Haioun, Corinne Eickhoff, Jens C. Young, Allen H. Gaulard, Philippe Piris, Miguel A. Oberley, Terry D. Rehrauer, William M. Kahl, Brad S. Malter, James S. Campo, Elias Delabie, Jan Gascoyne, Randy D. Rosenwald, Andreas Rimsza, Lisa Huang, James Braziel, Rita M. Jaffe, Elaine S. Wilson, Wyndham H. Staudt, Louis M. Vose, Julie M. Chan, Wing C. Weisenburger, Dennis D. Greiner, Timothy C. |
| description | The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL. |
| doi_str_mv | 10.1182/blood-2008-01-129783 |
| format | Article |
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TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2008-01-129783</identifier><identifier>PMID: 18559976</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Clinical Trials and Observations ; Cyclophosphamide - administration & dosage ; DNA Mutational Analysis ; Doxorubicin - administration & dosage ; Exons ; Female ; Humans ; International Cooperation ; Lymphoma, Large B-Cell, Diffuse - genetics ; Lymphoma, Large B-Cell, Diffuse - mortality ; Male ; Middle Aged ; Mutation ; Prednisolone - administration & dosage ; Prognosis ; Treatment Outcome ; Tumor Suppressor Protein p53 - genetics ; Vincristine - administration & dosage</subject><ispartof>Blood, 2008-10, Vol.112 (8), p.3088-3098</ispartof><rights>2008 American Society of Hematology</rights><rights>2008 by The American Society of Hematology 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-8fe191a5010b626d81ba63110dc944149191a9c2e5da5c5d48f97f53fe7ba4593</citedby><cites>FETCH-LOGICAL-c527t-8fe191a5010b626d81ba63110dc944149191a9c2e5da5c5d48f97f53fe7ba4593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18559976$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Young, Ken H.</creatorcontrib><creatorcontrib>Leroy, Karen</creatorcontrib><creatorcontrib>Møller, Michael B.</creatorcontrib><creatorcontrib>Colleoni, Gisele W.B.</creatorcontrib><creatorcontrib>Sánchez-Beato, Margarita</creatorcontrib><creatorcontrib>Kerbauy, Fábio R.</creatorcontrib><creatorcontrib>Haioun, Corinne</creatorcontrib><creatorcontrib>Eickhoff, Jens C.</creatorcontrib><creatorcontrib>Young, Allen H.</creatorcontrib><creatorcontrib>Gaulard, Philippe</creatorcontrib><creatorcontrib>Piris, Miguel A.</creatorcontrib><creatorcontrib>Oberley, Terry D.</creatorcontrib><creatorcontrib>Rehrauer, William M.</creatorcontrib><creatorcontrib>Kahl, Brad S.</creatorcontrib><creatorcontrib>Malter, James S.</creatorcontrib><creatorcontrib>Campo, Elias</creatorcontrib><creatorcontrib>Delabie, Jan</creatorcontrib><creatorcontrib>Gascoyne, Randy D.</creatorcontrib><creatorcontrib>Rosenwald, Andreas</creatorcontrib><creatorcontrib>Rimsza, Lisa</creatorcontrib><creatorcontrib>Huang, James</creatorcontrib><creatorcontrib>Braziel, Rita M.</creatorcontrib><creatorcontrib>Jaffe, Elaine S.</creatorcontrib><creatorcontrib>Wilson, Wyndham H.</creatorcontrib><creatorcontrib>Staudt, Louis M.</creatorcontrib><creatorcontrib>Vose, Julie M.</creatorcontrib><creatorcontrib>Chan, Wing C.</creatorcontrib><creatorcontrib>Weisenburger, Dennis D.</creatorcontrib><creatorcontrib>Greiner, Timothy C.</creatorcontrib><title>Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study</title><title>Blood</title><addtitle>Blood</addtitle><description>The purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.</description><subject>Aged</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Clinical Trials and Observations</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>DNA Mutational Analysis</subject><subject>Doxorubicin - administration & dosage</subject><subject>Exons</subject><subject>Female</subject><subject>Humans</subject><subject>International Cooperation</subject><subject>Lymphoma, Large B-Cell, Diffuse - genetics</subject><subject>Lymphoma, Large B-Cell, Diffuse - mortality</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Prednisolone - administration & dosage</subject><subject>Prognosis</subject><subject>Treatment Outcome</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Vincristine - administration & dosage</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kdFuFCEUhonR2G31DYzhBUY5zDAzeGGiTbUmTTSxXhMGDlsMM2yA2WRfwaeW7TZWb7wih__8_-HwEfIK2BuAkb-dQoy24YyNDYMGuBzG9gnZgOD1gnH2lGwYY33TyQHOyHnOPxmDruXiOTmDUQgph35Dfn0vaTVlTTrQXYrOB8w0Onr7TbR0iwvSeS26-LjkqqP1plAT_OJNNcS1mDgj9Qu13rk1Iw06bZF-bAyGQMNh3t3FWb-jeqlNBdNyH1WtJoagp5hqvUeay2oPL8gzp0PGlw_nBfnx6er28rq5-fr5y-WHm8YIPpRmdAgStGDApp73doRJ9y0As0Z2HXTyqErDUVgtjLDd6OTgROtwmHQnZHtB3p9yd-s0ozW4lLq92iU_63RQUXv1r7L4O7WNe8VFL6EXNaA7BZgUc07o_niBqSMbdc9GHdkoBurEptpe_z330fQA4_FhWLffe0wqG4-Lqb-e0BRlo___hN_qrKTg</recordid><startdate>20081015</startdate><enddate>20081015</enddate><creator>Young, Ken H.</creator><creator>Leroy, Karen</creator><creator>Møller, Michael B.</creator><creator>Colleoni, Gisele W.B.</creator><creator>Sánchez-Beato, Margarita</creator><creator>Kerbauy, Fábio R.</creator><creator>Haioun, Corinne</creator><creator>Eickhoff, Jens C.</creator><creator>Young, Allen H.</creator><creator>Gaulard, Philippe</creator><creator>Piris, Miguel A.</creator><creator>Oberley, Terry D.</creator><creator>Rehrauer, William M.</creator><creator>Kahl, Brad S.</creator><creator>Malter, James S.</creator><creator>Campo, Elias</creator><creator>Delabie, Jan</creator><creator>Gascoyne, Randy D.</creator><creator>Rosenwald, Andreas</creator><creator>Rimsza, Lisa</creator><creator>Huang, James</creator><creator>Braziel, Rita M.</creator><creator>Jaffe, Elaine S.</creator><creator>Wilson, Wyndham H.</creator><creator>Staudt, Louis M.</creator><creator>Vose, Julie M.</creator><creator>Chan, Wing C.</creator><creator>Weisenburger, Dennis D.</creator><creator>Greiner, Timothy C.</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</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>5PM</scope></search><sort><creationdate>20081015</creationdate><title>Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study</title><author>Young, Ken H. ; Leroy, Karen ; Møller, Michael B. ; Colleoni, Gisele W.B. ; Sánchez-Beato, Margarita ; Kerbauy, Fábio R. ; Haioun, Corinne ; Eickhoff, Jens C. ; Young, Allen H. ; Gaulard, Philippe ; Piris, Miguel A. ; Oberley, Terry D. ; Rehrauer, William M. ; Kahl, Brad S. ; Malter, James S. ; Campo, Elias ; Delabie, Jan ; Gascoyne, Randy D. ; Rosenwald, Andreas ; Rimsza, Lisa ; Huang, James ; Braziel, Rita M. ; Jaffe, Elaine S. ; Wilson, Wyndham H. ; Staudt, Louis M. ; Vose, Julie M. ; Chan, Wing C. ; Weisenburger, Dennis D. ; Greiner, Timothy C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-8fe191a5010b626d81ba63110dc944149191a9c2e5da5c5d48f97f53fe7ba4593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Aged</topic><topic>Antineoplastic Combined Chemotherapy Protocols - 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TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18559976</pmid><doi>10.1182/blood-2008-01-129783</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Blood, 2008-10, Vol.112 (8), p.3088-3098 |
| issn | 0006-4971 1528-0020 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2569165 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Aged Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - therapeutic use Clinical Trials and Observations Cyclophosphamide - administration & dosage DNA Mutational Analysis Doxorubicin - administration & dosage Exons Female Humans International Cooperation Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - mortality Male Middle Aged Mutation Prednisolone - administration & dosage Prognosis Treatment Outcome Tumor Suppressor Protein p53 - genetics Vincristine - administration & dosage |
| title | Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study |
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