Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial
Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial w...
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| Veröffentlicht in: | Leukemia 2020-07, Vol.34 (7), p.1760-1774 |
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| creator | Blakemore, Stuart J. Clifford, Ruth Parker, Helen Antoniou, Pavlos Stec-Dziedzic, Ewa Larrayoz, Marta Davis, Zadie Kadalyayil, Latha Colins, Andrew Robbe, Pauline Vavoulis, Dimitris Forster, Jade Carr, Louise Morilla, Ricardo Else, Monica Bryant, Dean McCarthy, Helen Walewska, Renata J. Steele, Andrew J. Chan, Jacqueline Speight, Graham Stankovic, Tanja Cragg, Mark S. Catovsky, Daniel Oscier, David G. Rose-Zerilli, Matthew J. J. Schuh, Anna Strefford, Jonathan C. |
| description | Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (
NFKBIE
) and 24% (
SF3B1
). Mutations beyond Sanger resolution ( |
| doi_str_mv | 10.1038/s41375-020-0723-2 |
| format | Article |
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NFKBIE
) and 24% (
SF3B1
). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with
KRAS
mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF
TP53
mutations, we assessed the clinical impact of
TP53
clonal architecture. Whilst ≥ 12% VAF
TP53
mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF
TP53
mutations and either wild type or ≥12% VAF
TP53
mut cases. Secondly, we identified biallelic
BIRC3
lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated
MAPK-ERK
genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-020-0723-2</identifier><identifier>PMID: 32015491</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45 ; 45/22 ; 45/23 ; 631/208/69 ; 631/67/1990/283/1895 ; 692/308/2056 ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Ataxia Telangiectasia Mutated Proteins - genetics ; Baculoviral IAP Repeat-Containing 3 Protein - genetics ; Biomarkers, Tumor - genetics ; Cancer ; Cancer Research ; Chemotherapy ; Chronic lymphocytic leukemia ; Clinical significance ; Clinical trials ; Cohort Studies ; Critical Care Medicine ; Cyclophosphamide - administration & dosage ; Extracellular signal-regulated kinase ; Extracellular Signal-Regulated MAP Kinases - genetics ; Follow-Up Studies ; Gene deletion ; Gene Expression Regulation, Neoplastic ; Gene mutations ; Genes ; Genetic aspects ; Genetic research ; Health services ; Hematology ; Humans ; Intensive ; Internal Medicine ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - mortality ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; MAP kinase ; MAP Kinase Signaling System - genetics ; Markers ; Medicine ; Medicine & Public Health ; Mutation ; Mutation rates ; Oncology ; p53 Protein ; Prognosis ; Survival analysis ; Survival Rate ; Tumor proteins ; Tumor Suppressor Protein p53 - genetics ; Vidarabine - administration & dosage ; Vidarabine - analogs & derivatives</subject><ispartof>Leukemia, 2020-07, Vol.34 (7), p.1760-1774</ispartof><rights>The Author(s) 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). 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-c596t-34707d1fdc398b2b380002ddffea31e2d87f334bd15d925f608213b2741567603</citedby><cites>FETCH-LOGICAL-c596t-34707d1fdc398b2b380002ddffea31e2d87f334bd15d925f608213b2741567603</cites><orcidid>0000-0002-3984-1507 ; 0000-0002-0972-2881 ; 0000-0003-0667-1596 ; 0000-0001-7108-0771</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41375-020-0723-2$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41375-020-0723-2$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32015491$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Blakemore, Stuart J.</creatorcontrib><creatorcontrib>Clifford, Ruth</creatorcontrib><creatorcontrib>Parker, Helen</creatorcontrib><creatorcontrib>Antoniou, Pavlos</creatorcontrib><creatorcontrib>Stec-Dziedzic, Ewa</creatorcontrib><creatorcontrib>Larrayoz, Marta</creatorcontrib><creatorcontrib>Davis, Zadie</creatorcontrib><creatorcontrib>Kadalyayil, Latha</creatorcontrib><creatorcontrib>Colins, Andrew</creatorcontrib><creatorcontrib>Robbe, Pauline</creatorcontrib><creatorcontrib>Vavoulis, Dimitris</creatorcontrib><creatorcontrib>Forster, Jade</creatorcontrib><creatorcontrib>Carr, Louise</creatorcontrib><creatorcontrib>Morilla, Ricardo</creatorcontrib><creatorcontrib>Else, Monica</creatorcontrib><creatorcontrib>Bryant, Dean</creatorcontrib><creatorcontrib>McCarthy, Helen</creatorcontrib><creatorcontrib>Walewska, Renata J.</creatorcontrib><creatorcontrib>Steele, Andrew J.</creatorcontrib><creatorcontrib>Chan, Jacqueline</creatorcontrib><creatorcontrib>Speight, Graham</creatorcontrib><creatorcontrib>Stankovic, Tanja</creatorcontrib><creatorcontrib>Cragg, Mark S.</creatorcontrib><creatorcontrib>Catovsky, Daniel</creatorcontrib><creatorcontrib>Oscier, David G.</creatorcontrib><creatorcontrib>Rose-Zerilli, Matthew J. J.</creatorcontrib><creatorcontrib>Schuh, Anna</creatorcontrib><creatorcontrib>Strefford, Jonathan C.</creatorcontrib><title>Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (
NFKBIE
) and 24% (
SF3B1
). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with
KRAS
mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF
TP53
mutations, we assessed the clinical impact of
TP53
clonal architecture. Whilst ≥ 12% VAF
TP53
mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF
TP53
mutations and either wild type or ≥12% VAF
TP53
mut cases. Secondly, we identified biallelic
BIRC3
lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated
MAPK-ERK
genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.</description><subject>45</subject><subject>45/22</subject><subject>45/23</subject><subject>631/208/69</subject><subject>631/67/1990/283/1895</subject><subject>692/308/2056</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Ataxia Telangiectasia Mutated Proteins - genetics</subject><subject>Baculoviral IAP Repeat-Containing 3 Protein - genetics</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Chemotherapy</subject><subject>Chronic lymphocytic leukemia</subject><subject>Clinical significance</subject><subject>Clinical trials</subject><subject>Cohort Studies</subject><subject>Critical Care Medicine</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Extracellular signal-regulated kinase</subject><subject>Extracellular Signal-Regulated MAP Kinases - genetics</subject><subject>Follow-Up Studies</subject><subject>Gene deletion</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene mutations</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Health services</subject><subject>Hematology</subject><subject>Humans</subject><subject>Intensive</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - genetics</subject><subject>Markers</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mutation</subject><subject>Mutation rates</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Prognosis</subject><subject>Survival analysis</subject><subject>Survival Rate</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Vidarabine - administration & dosage</subject><subject>Vidarabine - analogs & derivatives</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9UttuEzEUXCEQDYUP4AVZQuKJLb6sL8sDUohaqJKKKkqfLWdtZ1127WBvkPIJ_DVepbSNBMgP58hnZnw8mqJ4jeAZgkR8SBUinJYQwxJyTEr8pJigirOSUoqeFhMoBC9ZjauT4kVKtxCOQ_a8OCEYIlrVaFL8mnXOu0Z1ILmNdza3vjEgWLC6puQ9-Hy5nOUyXV0B5TW4ml7Py_PlHGyMNwk4D5o2hiwAun2_bUOzH8be7L4r0zv1EWg1KGBj6MHQGhCzRuhdMhrczMFieQFmi0UFhuhU97J4ZlWXzKu7elrcXJyvZl_Lxbcvl7PpomxozYaSVBxyjaxuSC3WeE0EhBBrba1RBBmsBbeEVGuNqK4xtQwKjMga8wpRxhkkp8Wng-52t-6NbowfourkNrpexb0MysnjiXet3ISfkhPMOGRZ4O2dQAw_diYN8jbsos87S1zxqhaMQvF_FBJCsLqCD6iN6ox03ob8ZJMdauSU4bw5hXxEnf0FlY_OJjfBG-vy_RHh3SNCa1Q3tCl0u8EFn46B6ABsYkgpGnvvA4JyzJg8ZEzmjMkxYxJnzpvHBt4z_oQqA_ABkPLIb0x8-Pq_VX8DKJbWeA</recordid><startdate>20200701</startdate><enddate>20200701</enddate><creator>Blakemore, Stuart J.</creator><creator>Clifford, Ruth</creator><creator>Parker, Helen</creator><creator>Antoniou, Pavlos</creator><creator>Stec-Dziedzic, Ewa</creator><creator>Larrayoz, Marta</creator><creator>Davis, Zadie</creator><creator>Kadalyayil, Latha</creator><creator>Colins, Andrew</creator><creator>Robbe, Pauline</creator><creator>Vavoulis, Dimitris</creator><creator>Forster, Jade</creator><creator>Carr, Louise</creator><creator>Morilla, Ricardo</creator><creator>Else, Monica</creator><creator>Bryant, Dean</creator><creator>McCarthy, Helen</creator><creator>Walewska, Renata J.</creator><creator>Steele, Andrew J.</creator><creator>Chan, Jacqueline</creator><creator>Speight, Graham</creator><creator>Stankovic, Tanja</creator><creator>Cragg, Mark S.</creator><creator>Catovsky, Daniel</creator><creator>Oscier, David G.</creator><creator>Rose-Zerilli, Matthew J. J.</creator><creator>Schuh, Anna</creator><creator>Strefford, Jonathan C.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3984-1507</orcidid><orcidid>https://orcid.org/0000-0002-0972-2881</orcidid><orcidid>https://orcid.org/0000-0003-0667-1596</orcidid><orcidid>https://orcid.org/0000-0001-7108-0771</orcidid></search><sort><creationdate>20200701</creationdate><title>Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial</title><author>Blakemore, Stuart J. ; Clifford, Ruth ; Parker, Helen ; Antoniou, Pavlos ; Stec-Dziedzic, Ewa ; Larrayoz, Marta ; Davis, Zadie ; Kadalyayil, Latha ; Colins, Andrew ; Robbe, Pauline ; Vavoulis, Dimitris ; Forster, Jade ; Carr, Louise ; Morilla, Ricardo ; Else, Monica ; Bryant, Dean ; McCarthy, Helen ; Walewska, Renata J. ; Steele, Andrew J. ; Chan, Jacqueline ; Speight, Graham ; Stankovic, Tanja ; Cragg, Mark S. ; Catovsky, Daniel ; Oscier, David G. ; Rose-Zerilli, Matthew J. J. ; Schuh, Anna ; Strefford, Jonathan C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c596t-34707d1fdc398b2b380002ddffea31e2d87f334bd15d925f608213b2741567603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>45</topic><topic>45/22</topic><topic>45/23</topic><topic>631/208/69</topic><topic>631/67/1990/283/1895</topic><topic>692/308/2056</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Ataxia Telangiectasia Mutated Proteins - genetics</topic><topic>Baculoviral IAP Repeat-Containing 3 Protein - genetics</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Chemotherapy</topic><topic>Chronic lymphocytic leukemia</topic><topic>Clinical significance</topic><topic>Clinical trials</topic><topic>Cohort Studies</topic><topic>Critical Care Medicine</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Extracellular signal-regulated kinase</topic><topic>Extracellular Signal-Regulated MAP Kinases - genetics</topic><topic>Follow-Up Studies</topic><topic>Gene deletion</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene mutations</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Health services</topic><topic>Hematology</topic><topic>Humans</topic><topic>Intensive</topic><topic>Internal Medicine</topic><topic>Leukemia</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - mortality</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - genetics</topic><topic>Markers</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mutation</topic><topic>Mutation rates</topic><topic>Oncology</topic><topic>p53 Protein</topic><topic>Prognosis</topic><topic>Survival analysis</topic><topic>Survival Rate</topic><topic>Tumor proteins</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Vidarabine - administration & dosage</topic><topic>Vidarabine - analogs & derivatives</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Blakemore, Stuart J.</creatorcontrib><creatorcontrib>Clifford, Ruth</creatorcontrib><creatorcontrib>Parker, Helen</creatorcontrib><creatorcontrib>Antoniou, Pavlos</creatorcontrib><creatorcontrib>Stec-Dziedzic, Ewa</creatorcontrib><creatorcontrib>Larrayoz, Marta</creatorcontrib><creatorcontrib>Davis, Zadie</creatorcontrib><creatorcontrib>Kadalyayil, Latha</creatorcontrib><creatorcontrib>Colins, Andrew</creatorcontrib><creatorcontrib>Robbe, Pauline</creatorcontrib><creatorcontrib>Vavoulis, Dimitris</creatorcontrib><creatorcontrib>Forster, Jade</creatorcontrib><creatorcontrib>Carr, Louise</creatorcontrib><creatorcontrib>Morilla, Ricardo</creatorcontrib><creatorcontrib>Else, Monica</creatorcontrib><creatorcontrib>Bryant, Dean</creatorcontrib><creatorcontrib>McCarthy, Helen</creatorcontrib><creatorcontrib>Walewska, Renata J.</creatorcontrib><creatorcontrib>Steele, Andrew J.</creatorcontrib><creatorcontrib>Chan, Jacqueline</creatorcontrib><creatorcontrib>Speight, Graham</creatorcontrib><creatorcontrib>Stankovic, Tanja</creatorcontrib><creatorcontrib>Cragg, Mark S.</creatorcontrib><creatorcontrib>Catovsky, Daniel</creatorcontrib><creatorcontrib>Oscier, David G.</creatorcontrib><creatorcontrib>Rose-Zerilli, Matthew J. J.</creatorcontrib><creatorcontrib>Schuh, Anna</creatorcontrib><creatorcontrib>Strefford, Jonathan C.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</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>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Blakemore, Stuart J.</au><au>Clifford, Ruth</au><au>Parker, Helen</au><au>Antoniou, Pavlos</au><au>Stec-Dziedzic, Ewa</au><au>Larrayoz, Marta</au><au>Davis, Zadie</au><au>Kadalyayil, Latha</au><au>Colins, Andrew</au><au>Robbe, Pauline</au><au>Vavoulis, Dimitris</au><au>Forster, Jade</au><au>Carr, Louise</au><au>Morilla, Ricardo</au><au>Else, Monica</au><au>Bryant, Dean</au><au>McCarthy, Helen</au><au>Walewska, Renata J.</au><au>Steele, Andrew J.</au><au>Chan, Jacqueline</au><au>Speight, Graham</au><au>Stankovic, Tanja</au><au>Cragg, Mark S.</au><au>Catovsky, Daniel</au><au>Oscier, David G.</au><au>Rose-Zerilli, Matthew J. J.</au><au>Schuh, Anna</au><au>Strefford, Jonathan C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2020-07-01</date><risdate>2020</risdate><volume>34</volume><issue>7</issue><spage>1760</spage><epage>1774</epage><pages>1760-1774</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (
NFKBIE
) and 24% (
SF3B1
). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with
KRAS
mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF
TP53
mutations, we assessed the clinical impact of
TP53
clonal architecture. Whilst ≥ 12% VAF
TP53
mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF
TP53
mutations and either wild type or ≥12% VAF
TP53
mut cases. Secondly, we identified biallelic
BIRC3
lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated
MAPK-ERK
genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32015491</pmid><doi>10.1038/s41375-020-0723-2</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-3984-1507</orcidid><orcidid>https://orcid.org/0000-0002-0972-2881</orcidid><orcidid>https://orcid.org/0000-0003-0667-1596</orcidid><orcidid>https://orcid.org/0000-0001-7108-0771</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2020-07, Vol.34 (7), p.1760-1774 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7326706 |
| source | MEDLINE; SpringerLink Journals |
| subjects | 45 45/22 45/23 631/208/69 631/67/1990/283/1895 692/308/2056 Antineoplastic Combined Chemotherapy Protocols - therapeutic use Ataxia Telangiectasia Mutated Proteins - genetics Baculoviral IAP Repeat-Containing 3 Protein - genetics Biomarkers, Tumor - genetics Cancer Cancer Research Chemotherapy Chronic lymphocytic leukemia Clinical significance Clinical trials Cohort Studies Critical Care Medicine Cyclophosphamide - administration & dosage Extracellular signal-regulated kinase Extracellular Signal-Regulated MAP Kinases - genetics Follow-Up Studies Gene deletion Gene Expression Regulation, Neoplastic Gene mutations Genes Genetic aspects Genetic research Health services Hematology Humans Intensive Internal Medicine Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - mortality Leukemia, Lymphocytic, Chronic, B-Cell - pathology MAP kinase MAP Kinase Signaling System - genetics Markers Medicine Medicine & Public Health Mutation Mutation rates Oncology p53 Protein Prognosis Survival analysis Survival Rate Tumor proteins Tumor Suppressor Protein p53 - genetics Vidarabine - administration & dosage Vidarabine - analogs & derivatives |
| title | Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial |
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