TY - JOUR
T1 - Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia
T2 - data from the randomised UK LRF CLL4 trial
AU - Blakemore, Stuart J.
AU - Clifford, Ruth
AU - Parker, Helen
AU - Antoniou, Pavlos
AU - Stec-Dziedzic, Ewa
AU - Larrayoz, Marta
AU - Davis, Zadie
AU - Kadalyayil, Latha
AU - Colins, Andrew
AU - Robbe, Pauline
AU - Vavoulis, Dimitris
AU - Forster, Jade
AU - Carr, Louise
AU - Morilla, Ricardo
AU - Else, Monica
AU - Bryant, Dean
AU - McCarthy, Helen
AU - Walewska, Renata J.
AU - Steele, Andrew J.
AU - Chan, Jacqueline
AU - Speight, Graham
AU - Stankovic, Tanja
AU - Cragg, Mark S.
AU - Catovsky, Daniel
AU - Oscier, David G.
AU - Rose-Zerilli, Matthew J.J.
AU - Schuh, Anna
AU - Strefford, Jonathan C.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078950621&partnerID=8YFLogxK
U2 - 10.1038/s41375-020-0723-2
DO - 10.1038/s41375-020-0723-2
M3 - Article
C2 - 32015491
AN - SCOPUS:85078950621
SN - 0887-6924
VL - 34
SP - 1760
EP - 1774
JO - Leukemia
JF - Leukemia
IS - 7
ER -