Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome
Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patie...
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| creator | Fischer, Nicholas W Prodeus, Aaron Tran, James Malkin, David Gariépy, Jean |
| description | Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain. |
| doi_str_mv | 10.1093/jnci/djy114 |
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Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.</description><identifier>ISSN: 0027-8874</identifier><identifier>ISSN: 1460-2105</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djy114</identifier><identifier>PMID: 29955864</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Brief Communication ; Genetic Association Studies ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Li-Fraumeni Syndrome - genetics ; Li-Fraumeni Syndrome - mortality ; Models, Molecular ; Mutation ; Prognosis ; Protein Conformation ; Protein Multimerization ; Structure-Activity Relationship ; Survival Analysis ; Tumor Suppressor Protein p53 - chemistry ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2018-12, Vol.110 (12), p.1418-1421</ispartof><rights>The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-8b74c152297f0fcf6af712914b068c943b9ce4424909854f1932717c1fb2507c3</citedby><cites>FETCH-LOGICAL-c381t-8b74c152297f0fcf6af712914b068c943b9ce4424909854f1932717c1fb2507c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,778,782,883,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29955864$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fischer, Nicholas W</creatorcontrib><creatorcontrib>Prodeus, Aaron</creatorcontrib><creatorcontrib>Tran, James</creatorcontrib><creatorcontrib>Malkin, David</creatorcontrib><creatorcontrib>Gariépy, Jean</creatorcontrib><title>Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>J Natl Cancer Inst</addtitle><description>Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.</description><subject>Brief Communication</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Germ-Line Mutation</subject><subject>Humans</subject><subject>Li-Fraumeni Syndrome - genetics</subject><subject>Li-Fraumeni Syndrome - mortality</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>Prognosis</subject><subject>Protein Conformation</subject><subject>Protein Multimerization</subject><subject>Structure-Activity Relationship</subject><subject>Survival Analysis</subject><subject>Tumor Suppressor Protein p53 - chemistry</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>0027-8874</issn><issn>1460-2105</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtrGzEURkVoqJ20q-yDloUwsV4zkjYF1-QFBi-SbCs0spTIzEiupGnwv88EJya5m7v4Dt-9cAA4w-gSI0lnm2D8bL3ZYcyOwBSzBlUEo_obmCJEeCUEZxNwkvMGjSMJ-w4mRMq6Fg2bgr_znKPxuvgY4B9bXqwNsDxbuOr8U-xt8gbeF12GDKOD25pCHdZw0fngje7gaihmpDL0AS59dZ300Nvg4f0urNMY_ADHTnfZ_nzfp-Dx-uphcVstVzd3i_myMlTgUomWM4NrQiR3yBnXaMcxkZi1qBFGMtpKYxkjTCIpauawpIRjbrBrSY24oafg9753O7S9XRsbStKd2ibf67RTUXv1NQn-WT3F_6ohknDRjAW_3gtS_DfYXFTvs7Fdp4ONQ1YENURQihs0ohd71KSYc7LucAYj9WZEvRlReyMjff75swP7oYC-AnyuiIQ</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Fischer, Nicholas W</creator><creator>Prodeus, Aaron</creator><creator>Tran, James</creator><creator>Malkin, David</creator><creator>Gariépy, Jean</creator><general>Oxford University Press</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><scope>5PM</scope></search><sort><creationdate>20181201</creationdate><title>Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome</title><author>Fischer, Nicholas W ; Prodeus, Aaron ; Tran, James ; Malkin, David ; Gariépy, Jean</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-8b74c152297f0fcf6af712914b068c943b9ce4424909854f1932717c1fb2507c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Brief Communication</topic><topic>Genetic Association Studies</topic><topic>Genetic Predisposition to Disease</topic><topic>Germ-Line Mutation</topic><topic>Humans</topic><topic>Li-Fraumeni Syndrome - genetics</topic><topic>Li-Fraumeni Syndrome - mortality</topic><topic>Models, Molecular</topic><topic>Mutation</topic><topic>Prognosis</topic><topic>Protein Conformation</topic><topic>Protein Multimerization</topic><topic>Structure-Activity Relationship</topic><topic>Survival Analysis</topic><topic>Tumor Suppressor Protein p53 - chemistry</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fischer, Nicholas W</creatorcontrib><creatorcontrib>Prodeus, Aaron</creatorcontrib><creatorcontrib>Tran, James</creatorcontrib><creatorcontrib>Malkin, David</creatorcontrib><creatorcontrib>Gariépy, Jean</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fischer, Nicholas W</au><au>Prodeus, Aaron</au><au>Tran, James</au><au>Malkin, David</au><au>Gariépy, Jean</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>J Natl Cancer Inst</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>110</volume><issue>12</issue><spage>1418</spage><epage>1421</epage><pages>1418-1421</pages><issn>0027-8874</issn><issn>1460-2105</issn><eissn>1460-2105</eissn><abstract>Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>29955864</pmid><doi>10.1093/jnci/djy114</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Brief Communication Genetic Association Studies Genetic Predisposition to Disease Germ-Line Mutation Humans Li-Fraumeni Syndrome - genetics Li-Fraumeni Syndrome - mortality Models, Molecular Mutation Prognosis Protein Conformation Protein Multimerization Structure-Activity Relationship Survival Analysis Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome |
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