Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia

Knight, Samantha J. L.; Yau, Christopher; Clifford, Ruth; Timbs, Adele; Akha, Elham Sadighi; Dreau, Hélène; Burns, Adam; Ciria, Cristian; Oscier, David; Pettitt, Andrew R.; Dutton, Susan; Holmes, Connor; Taylor, Jenny C.; Cazier, Jean‐Baptiste; Schuh, Anna

doi:10.1038/leu.2012.13

Cited by 64 publications

(64 citation statements)

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“…3,9,18,39 Using our targeted NGS approach on bulk leukemia cells, the likely subclonal distribution of the MH profile could only be inferred. Longitudinal genome-wide studies including multiple time points or single cell approaches are required to precisely reconstruct the tumor phylogeny.…”

Section: Discussionmentioning

confidence: 99%

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Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

Guièze

Robbe

Clifford

et al. 2015

Blood

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Key Points• Targeted NGS of relapsed/ refractory CLL reveals a high incidence of concurrent mutations that mostly affect the TP53, ATM, and SF3B1 genes.• Concurrent mutations of the TP53, ATM, and/or SF3B1 genes confer short survival in patients with relapsed/ refractory CLL.Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ‡2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ‡2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiplehit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P 5 .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome. (Blood. 2015;126(18):2110-2117 IntroductionChronic lymphocytic leukemia (CLL) is characterized by its unique immunophenotype of CD19sIg dim expressing clonal mature B cells and also by a highly variable clinical course. With the emergence of new classes of drugs such as the inhibitor of phosphatidylinositol 3-kinase, idelalisib, 1 and the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, 2 available treatment options have increased significantly and allow us to begin to develop models of treatment stratification. Over the last 3 years, the CLL genome has been thoroughly characterized by next-generation sequencing (NGS).3 Pioneer reports using this approach unraveled somatic mutations recurrently targeting multiple genes, among which TP53, SF3B1, NOTCH1, MYD88, and ATM were the most frequent. [4][5][6][7][8][9] Large retrospective studies in untreated patients from historical cohorts have recently shown the adverse prognostic impact of the TP53, NOTCH1, and SF3B1 mutations on time to treatment and overall survival (OS). [10][11][12] In addition, mutations in these genes may also be associated with poor progression-free survival (PFS) in frontline patients treated in prospective trials. 13,14 Conversely, the pejorative impact of TP53, SF3B1, and NOTCH1 mutations on the clinical outcome of patients with relapsed/ refractory (R/R) CLL is controversial. [15][16][17] Compared with untreated CLL, relapse, as advanced disease, may be associated with a high level of genomic diversification. 9,18 This process might result in For personal use only. on May 11, 2018. by guest www.bloodjournal.org From accumulation and co-occurrence of these or other genomic events leading to interactions that could be of prognostic relevance. Here, w...

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Section: Discussionmentioning

confidence: 99%

“…However, there is evidence from previous whole genome array studies that there is a strong correlation between genomic complexity and the presence of TP53 disruption. 39,40 Therefore, large patient cohorts will be required to unravel potential independence of these phenomena.…”

Section: Discussionmentioning

confidence: 99%

Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

Guièze

Robbe

Clifford

et al. 2015

Blood

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“…It is not known at the moment whether the mutation order is important for the clinical course but similar to clonal, subclonal mutations may carry prognostic value [35]. Integrating genomic data from sequential samples, three types of CLL evolution were identified, which associate with patient's course: (i) no evolution, (ii) linear evolution, and (iii) branched evolution [9,11,26,[129][130][131][132]. Branched evolution is associated with disease evolution and dismal prognosis, probably because the generated genetic diversity allows for a more efficient selection of fitted cells.…”

Section: Intrapatient Heterogeneitymentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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“…Using conventional prognostic markers, all 3 patients belonged to an intermediate risk group (IgVH unmutated, no TP53 abnormalities, no genomic complexity [32][33][34][35][36] ; supplemental Table 1) and were treated with similar combinations of alkylating agents, purine analogues, and immunotherapy.…”

Section: Patterns Of Clonal Evolution Are Heterogeneous In Cllmentioning

confidence: 99%

Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns

Schuh

Becq

Humphray

et al. 2012

Blood

302

312

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Chronic lymphocytic leukemia is characterized by relapse after treatment and chemotherapy resistance. Similarly, in other malignancies leukemia cells accumulate mutations during growth, forming heterogeneous cell populations that are subject to Darwinian selection and may respond differentially to treatment. There is therefore a clinical need to monitor changes in the subclonal composition of cancers during disease progression. Here, we use whole-genome sequencing to track subclonal heterogeneity in 3 chronic lymphocytic leukemia patients subjected to repeated cycles of therapy. We reveal different somatic mutation profiles in each patient and use these to establish probable hierarchical patterns of subclonal evolution, to identify subclones that decline or expand over time, and to detect founder mutations. We show that clonal evolution patterns are heterogeneous in individual patients. We conclude that genome sequencing is a powerful and sensitive approach to monitor disease progression repeatedly at the molecular level. IntroductionDespite significant progress in the management of lymphomas and leukemias, relapse remains the major cause of death. Increased use of expensive targeted therapies and toxic chemotherapies (especially in the elderly) confronts us with an urgent need to improve response prediction for all cancer patients to reduce side effects and costs from ineffective treatment. Current diagnostic approaches to treatment selection, response monitoring, and relapse prediction are limited to single genes and apply only to a minority of hematologic cancers. This is at odds with modern concepts of tumor propagation and maintenance, which propose that every cell in an individual cancer is characterized by a combination of mutation events that comprise tumorigenic (driver) mutations, passive (passenger) mutations, and possibly predisposing germline risk variants. Cancer cells propagate and diversify during tumor growth, resulting in a heterogeneous population of genotypically and phenotypically distinct subclones that are related in a hierarchical lineage. As the composition of the local environment changes, for example as a consequence of drug treatment, tumor cell populations adapt and evolve by Darwinian selection. [1][2][3] Whole-genome sequencing (WGS) of a single tumor sample can be used to generate a comprehensive catalog of variants that provides a snapshot of the cell population en masse at a particular time point. 2,4-6 However, over time and with continued evolution of the cancer, this snapshot becomes progressively less representative of the disease. Recent reports have described whole-tumor genomes from single patients or cohorts of individuals mostly at single time points and irrespective of treatment. [7][8][9][10] This approach has enabled identification of mutations representative and in some cases highly predictive of histologic cancer type, outcome, and/or treatment response. [11][12][13][14][15] Comparison of sequence data from primary and metastatic tumor samples, or from multiple lo...

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Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia

Cited by 64 publications

References 47 publications

Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

Chronic lymphocytic leukemia: Time to go past genomics?

Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns

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