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.
Highlights
These authors contributed : Anna Schuh, Jonathan C
We report targeted resequencing analysis of 22 genes known to be recurrently mutated in chronic lymphocytic leukaemia (CLL) in the UK CLL4 clinical trial
Our study confirms previous studies incorporating samples from this patient cohort showing the impact of TP53ab on progression-free survival (PFS) and overall survival (OS) in multivariate analysis (MVA), SF3B1, EGR2 [25, 26], RPS15 [1, 24] and NFKBIE [25, 28, 42] mutations on OS in univariate analysis, with SF3B1 and EGR2 mutations retained as independent markers of OS in MVA
Summary
Mutations of specific genes including TP53 [4,5,6,7,8,9,10], ATM [9, 11,12,13,14], BIRC3 [9, 15, 16], SF3B1 [9, 17,18,19,20], NOTCH1 [1, 9, 15, 17, 20,21,22,23], RPS15 [2, 24], EGR2 [25, 26] and KRAS [27, 28] are associated with poorer outcome, especially shorter time to first treatment or overall survival (OS). Important findings include the failure of
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