Highly similar genomic landscapes in monoclonal b-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations

A Agathangelidis, V Ljungström, L Scarfò, Claudia Fazi, M Gounari, T Pandzic, LA Sutton, K Stamatopoulos, G Tonon, R Rosenquist, P Ghia

Research output: Contribution to journalArticle

Abstract

Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we performed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia ( > 10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unre-ported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. © 2018 Ferrata Storti Foundation.
Original languageEnglish
Pages (from-to)865-873
Number of pages9
JournalHaematologica
Volume103
Issue number5
DOIs
Publication statusPublished - 2018

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Lymphocytosis
Mutation Rate
B-Cell Chronic Lymphocytic Leukemia
Mutation
B-Lymphocytes
High-Throughput Nucleotide Sequencing
Hematopoietic Stem Cells
Genes
Genome
Phenotype

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Highly similar genomic landscapes in monoclonal b-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations. / Agathangelidis, A; Ljungström, V; Scarfò, L; Fazi, Claudia; Gounari, M; Pandzic, T; Sutton, LA; Stamatopoulos, K; Tonon, G; Rosenquist, R; Ghia, P.

In: Haematologica, Vol. 103, No. 5, 2018, p. 865-873.

Research output: Contribution to journalArticle

Agathangelidis, A ; Ljungström, V ; Scarfò, L ; Fazi, Claudia ; Gounari, M ; Pandzic, T ; Sutton, LA ; Stamatopoulos, K ; Tonon, G ; Rosenquist, R ; Ghia, P. / Highly similar genomic landscapes in monoclonal b-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations. In: Haematologica. 2018 ; Vol. 103, No. 5. pp. 865-873.
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AU - Gounari, M

AU - Pandzic, T

AU - Sutton, LA

AU - Stamatopoulos, K

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AU - Rosenquist, R

AU - Ghia, P

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AB - Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we performed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia ( > 10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unre-ported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. © 2018 Ferrata Storti Foundation.

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