Clinical impact of small subclones harboring
 NOTCH1
 ,
 SF3B1
 or
 BIRC3
 mutations in chronic lymphocytic leukemia

Rasi, Silvia; Khiabanian, Hossein; Ciardullo, Carmela; Terzi-di-Bergamo, Lodovico; Monti, Sara; Spina, Valeria; Bruscaggin, Alessio; Cerri, Michaela; Deambrogi, Clara; Martuscelli, Lavinia; Biasi, Alessandra; Spaccarotella, Elisa; Paoli, Lorenzo De; Gattei, Valter; Foà, Robin; Rabadán, Raúl; Gaïdano, Gianluca; Rossi, Davide

doi:10.3324/haematol.2015.136051

Cited by 35 publications

(32 citation statements)

References 10 publications

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“…Subclonal TP53 mutations have been shown to similarly confer poor prognosis (Nadeu et al, 2016;Rasi et al, 2016). NGS approaches are mandatory given the extremely low mutation levels, undetectable by classical analyses impact prognosis (Hallek et al, 2008;Pospisilova et al, 2012;Rossi et al, 2014;Malcikova et al, 2015;Amin et al, 2016;Edelmann et al, 2016;Nadeu et al, 2016;Rasi et al, 2016), and argue for a need to repeat TP53 inactivation analysis prior to any subsequent line of therapy (Hallek et al, 2008;Pospisilova et al, 2012). The BTK inhibitor, ibrutinib, the phosphatidylinositol 3-kinase delta inhibitor, idelalisib and the BCL2 inhibitor, venetoclax, represent therapeutic options (Roberts et al, 2016).…”

Section: Somatic Mutations and Clinical Impactmentioning

confidence: 99%

Chronic lymphocytic leukaemia genomics and the precision medicine era

2017

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Massive genomic analyses have underscored the diversity of chronic lymphocytic leukaemia (CLL) between patients. Genetic heterogeneity of tumour clones within a patient may fuel tumour evolution. Several recurrently deregulated intra-cellular pathways are candidates for targeted therapies that are very promising and are dramatically changing clinical patients' perspectives. In this review we present an overview of the genetic and epigenetic features of CLL and their clinical and biological implications.

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Section: Somatic Mutations and Clinical Impactmentioning

confidence: 99%

Chronic lymphocytic leukaemia genomics and the precision medicine era

2017

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“…Next-generation sequencing (NGS) techniques documented that, besides the aforementioned genes, a number of previously unidentified genes may be mutated in CLL and that the disruption of putative core cellular pathways represents an important mechanism promoting disease progression and drug resistance [ 23 – 26 ]. NGS may detect minor cell populations (subclones) harboring a variety of gene mutations, including NOTCH1 , SF3B1 , BIRC3 , and TP53 mutations, the latter having a negative prognostic impact that was similar to TP53 clonal mutations [ 27 – 29 ] as detected by conventional sequencing techniques (i.e., Sanger sequencing).…”

Section: Introductionmentioning

confidence: 99%

Extensive next-generation sequencing analysis in chronic lymphocytic leukemia at diagnosis: clinical and biological correlations

et al. 2016

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BackgroundIn chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations.MethodsWe performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression. The genomic DNA from peripheral blood samples of 200 consecutive CLL patients was analyzed using Ion Torrent Personal Genome Machine, a NGS platform that uses semiconductor sequencing technology. Karyotype analysis was performed using efficient mitogens.ResultsMutations were detected in 42.0 % of cases with 42.8 % of mutated patients presenting 2 or more mutations. The presence of mutations by NGS was associated with unmutated IGHV gene (p = 0.009), CD38 positivity (p = 0.010), risk stratification by fluorescence in situ hybridization (FISH) (p < 0.001), and the complex karyotype (p = 0.003). A high risk as assessed by FISH analysis was associated with mutations affecting TP53 (p = 0.012), BIRC3 (p = 0.003), and FBXW7 (p = 0.003) while the complex karyotype was significantly associated with TP53, ATM, and MYD88 mutations (p = 0.003, 0.018, and 0.001, respectively). By multivariate analysis, the multi-hit profile (≥2 mutations by NGS) was independently associated with a shorter time to first treatment (p = 0.004) along with TP53 disruption (p = 0.040), IGHV unmutated status (p < 0.001), and advanced stage (p < 0.001). Advanced stage (p = 0.010), TP53 disruption (p < 0.001), IGHV unmutated status (p = 0.020), and the complex karyotype (p = 0.007) were independently associated with a shorter overall survival.ConclusionsAt diagnosis, an extensive biologic characterization including NGS and karyotype analyses using novel mitogens may offer new perspectives for a better refinement of risk stratification that could be of help in the clinical management of CLL patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0320-z) contains supplementary material, which is available to authorized users.

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“…Its application to 309 newly diagnosed CLL patients identified small sub-clonal prognostic mutations in four frequently mutated drivers of this neoplasm, present in 2 out of 1,000 wild-type alleles. These mutations were missed by traditional Sanger sequencing, but were validated by independent deep sequencing and allele-specific PCR 33,34 .…”

Section: Resultsmentioning

confidence: 99%

On statistical modeling of sequencing noise in high depth data to assess tumor evolution

Rabadán

Bhanot

Marsilio

et al. 2017

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One cause of cancer mortality is tumor evolution to therapy-resistant disease. First line therapy often targets the dominant clone, and drug resistance can emerges from preexisting clones that gain fitness through therapy-induced natural selection. Such mutations may be identified using targeted sequencing assays by analysis of noise in high-depth data. Here, we develop a comprehensive, unbiased model for sequencing error background. We find that noise in sufficiently deep DNA sequencing data can be approximated by aggregating negative binomial distributions. Mutations with frequencies above noise may have prognostic value. We evaluate our model with simulated exponentially expanded populations as well as data from cell line and patient sample dilution experiments, demonstrating its utility in prognosticating tumor progression. Our results may have the potential to identify significant mutations that can cause recurrence. These results are relevant in the pretreatment clinical setting to determine appropriate therapy and prepare for potential recurrence pretreatment.

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Clinical impact of small subclones harboring NOTCH1 , SF3B1 or BIRC3 mutations in chronic lymphocytic leukemia

Cited by 35 publications

References 10 publications

Chronic lymphocytic leukaemia genomics and the precision medicine era

Chronic lymphocytic leukaemia genomics and the precision medicine era

Extensive next-generation sequencing analysis in chronic lymphocytic leukemia at diagnosis: clinical and biological correlations

On statistical modeling of sequencing noise in high depth data to assess tumor evolution

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