Blakemore, Stuart J., Clifford, Ruth, Parker, Helen, Antoniou, Pavlos, Stec-Dziedzic, Ewa, Larrayoz, Marta ORCID: 0000-0001-6097-8244, 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 and Strefford, Jonathan C. (2020). Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial. Leukemia, 34 (7). S. 1760 - 1775. LONDON: SPRINGERNATURE. ISSN 1476-5551

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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 TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst >= 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between TP53 mutations and either wild type or >= 12% VAF TP53mut 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Blakemore, Stuart J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clifford, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parker, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, PavlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stec-Dziedzic, EwaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larrayoz, MartaUNSPECIFIEDorcid.org/0000-0001-6097-8244UNSPECIFIED
Davis, ZadieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kadalyayil, LathaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colins, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robbe, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vavoulis, DimitrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forster, JadeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carr, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morilla, RicardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Else, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bryant, DeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCarthy, HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walewska, Renata J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steele, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, JacquelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speight, GrahamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stankovic, TanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cragg, Mark S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catovsky, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oscier, David G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rose-Zerilli, Matthew J. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuh, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strefford, Jonathan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-345693
DOI: 10.1038/s41375-020-0723-2
Journal or Publication Title: Leukemia
Volume: 34
Number: 7
Page Range: S. 1760 - 1775
Date: 2020
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1476-5551
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RECURRENT MUTATIONS; SF3B1 MUTATIONS; SURVIVAL; IMPACT; NOTCH1; PROGRESSION; CHEMOTHERAPY; DISRUPTION; PREDICTOR; EVOLUTIONMultiple languages
Oncology; HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34569

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