The Broad Spectrum of Mutations in CLL: Evidence of Multiclonality and Novel Mutation Hotspots.

Fiche publication

Date publication

mai 2023

Journal

Human mutation

Auteurs

Membres identifiés du Cancéropôle Est :
Dr CORNILLET-LEFEBVRE Pascale

Tous les auteurs :
Lazarian G, Leroy B, Theves F, Hormi M, Letestu R, Eclache V, Tueur G, Ameur A, Bidet A, Cornillet-Lefebvre P, Davi F, Delabesse E, Estienne MH, Etancelin P, Kosmider O, Laibe S, Muller M, Nadal N, Naguib D, Pastoret C, Poulain S, Sujobert P, Veronese L, Imache S, Lefebvre V, Cymbalista F, Baran-Marszak F, Soussi T,

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/40225169

Résumé

aberrations are a major predictive factor of resistance to chemoimmunotherapy in chronic lymphocytic leukemia (CLL), and an assessment of them before each line of treatment is required for theranostic stratification. Acquisition of subclonal abnormalities underlies the evolution of CLL. To better characterize the distribution, combination, and impact of variants in CLL, 1,056 variants collected from 683 patients included in a multicenter collaborative study in France were analyzed and compared to UMD_CLL, a dataset built from published articles collectively providing 5,173 variants detected in 3,808 patients. Our analysis confirmed the presence of several CLL-specific hotspot mutations, including a two-base pair deletion in codon 209 and a missense variant at codon 234, the latter being associated with alkylating treatment. Our analysis also identified a novel CLL-specific variant in the splice acceptor signal of intron 6 leading to the use of a cryptic splice site, similarly utilized by to generate p53psi, a naturally truncated p53 isoform localized in the mitochondria. Examination of both UMD_CLL and several recently released large-scale genomic analyses of CLL patients confirmed that this splice variant is highly enriched in this disease when compared to other cancer types. Using a TP53-specific single-nucleotide polymorphism, we also confirmed that copy-neutral loss of heterozygosity is frequent in CLL. This event can lead to misinterpretation of status. Unlike other cancers, CLL displayed a high proportion of patients harboring multiple variants. Using both in silico analysis and single molecule smart sequencing, we demonstrated the coexistence of distinct subclones harboring mutations on distinct alleles. In summary, our study provides a detailed mutational architecture in CLL and gives insights into how treatments may shape the genetic landscape of CLL patients.