Next generation sequencing and copy number analysis provide insights into the complexity of the CLL coding genome, and reveal an association between NOTCH1 mutational activation and poor prognosis.

No abstract

The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a trainingvalidation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring ؉12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions. (Blood. 2013;121(8):1403-1412) Continuing Medical Education onlineThis activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and the American Society of Hematology. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™ . Physicians should claim only the credit commensurate with the extent of their participationin the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 1482. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in IntroductionThe course of chronic lymphocytic leukemia (CLL) ranges from very indolent with a nearly normal life expectancy to rapidly progressive leading to early death. 1,2 To better understand the genetic basis of CLL heterogeneity and improve pr...

Notch2 mutations represent the most frequent lesion in splenic marginal zone lymphoma.

The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabinerefractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P ‫؍‬ .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700), and were predictive of a poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (P ‫؍‬ . IntroductionThe clinical course of chronic lymphocytic leukemia (CLL) ranges from a very indolent disorder with a normal lifespan for the patient to a rapidly progressive disease that leads to death. Occasionally, CLL undergoes a transformation to Richter syndrome (RS). [1][2][3] The variable clinical course of CLL is driven, at least in part, by the disease's immunogenetic and molecular heterogeneity. 4 Despite recent advances, the genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of CLL and do not entirely explain the development of severe complications, such as chemorefractoriness, which still represent unmet clinical needs. 5 In approximately 40% of cases, refractoriness to fludarabine is attributable to the disruption of TP53, but in a sizeable fraction of patients, the molecular basis of this aggressive phenotype remains unclear. 6 Recently, 2 independent studies of the CLL coding genome investigated at disease presentation have revealed a restricted number of mutated genes, including NOTCH1. 7,8 These studies have provided a proof of concept that, similar to other malignancies, genome-wide mutational analysis might identify novel lesions of biologic and clinical relevance in CLL. On these grounds, we have embarked on the investigation of the coding genome of fludarabine-refractory CLL to identify genetic lesions associated with chemorefractoriness. The initial phases of this analysis have revealed recurrent mutations of SF3B1, a critical component of the cell spliceosome, pointing to the potential involvement of splicing regulation in CLL pathogenesis and chemorefractoriness. Methods PatientsThe study population comprised 3 cohorts representative of different disease phases: (1) fludarabine-refractory CLL (n ϭ 59), including cases (n ϭ 11) subjected to whole-exome sequencing (supplemental Table 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article); (2) a consecutive series of newly diagnosed and previously untreated patients with CLL (n ϭ 301; supplemental Table 2 For pers...