Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial

Stuart J. Blakemore, Ruth Clifford, Helen Parker, Pavlos Antoniou, Ewa Stec-Dziedzic, Marta Larrayoz, Zadie Davis, Latha Kadalyayil, Andrew Colins, Pauline Robbe, Dimitris Vavoulis, Jade Forster, Louise Carr, Ricardo Morilla, Monica Else, Dean Bryant, Helen McCarthy, Renata J. Walewska, Andrew J. Steele, Jacqueline ChanGraham Speight, Tanja Stankovic, Mark S. Cragg, Daniel Catovsky, David G. Oscier, Matthew J.J. Rose-Zerilli, Anna Schuh, Jonathan C. Strefford

Research output: Contribution to journalArticlepeer-review

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 TP53mut 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 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.

Original languageEnglish
Pages (from-to)1760-1774
Number of pages15
JournalLeukemia
Volume34
Issue number7
DOIs
Publication statusPublished - 1 Jul 2020
Externally publishedYes

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