Genomic and epigenomic heterogeneity in chronic lymphocytic leukemia

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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...

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Guièze

Robbe

Clifford

et al. 2015

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“…68 For these reasons, analysis of TP53 and IGHV mutational status has recently been incorporated into a new International Prognostic Index for treatment-naive CLL patients (the CLL-International Prognostic Index). 69 Finally, sequencing of .100 whole genomes 70,71 and .500 whole exomes [71][72][73][74] of CLL patients has now revealed recurrent somatic mutations, including those potentially associated with adverse outcome such as mutations in NOTCH1, SF3B1, and ATM (discussed in several excellent recent reviews: Rodríguez et al, 75 Kipps et al, 76 Guièze and Wu, 77 and Lazarian et al 78 ; Table 3). With the exception of TP53 alterations, however, detection of other mutations in CLL is not currently included in routine clinical practice in CLL as their prognostic relevance is not clear.…”

Section: Lymphoma and Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Diagnosis and classification of hematologic malignancies on the basis of genetics

Taylor¹,

Xiao²,

Abdel-Wahab

2017

194

149

Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia. Among patients with MDS, detection of mutations in SF3B1 define a subgroup of patients with the ring sideroblast form of MDS and a favorable prognosis. For patients with MPNs, detection of the BCR-ABL1 fusion delineates chronic myeloid leukemia from classic BCR-ABL1− MPNs, which are largely defined by mutations in JAK2, CALR, or MPL. In the B-cell lymphomas, detection of characteristic rearrangements involving MYC in Burkitt lymphoma, BCL2 in follicular lymphoma, and MYC/BCL2/BCL6 in high-grade B-cell lymphomas are essential for diagnosis. In T-cell lymphomas, anaplastic large-cell lymphoma is defined by mutually exclusive rearrangements of ALK, DUSP22/IRF4, and TP63. Genetic alterations affecting TP53 and the mutational status of the immunoglobulin heavy-chain variable region are important in clinical management of chronic lymphocytic leukemia. Additionally, detection of BRAFV600E mutations is helpful in the diagnosis of classical hairy cell leukemia and a number of histiocytic neoplasms. Numerous additional examples provided here demonstrate how clinical evaluation of genomic alterations have refined classification of myeloid neoplasms and major forms of lymphomas arising from B, T, or natural killer cells.

“…1 In recent years, nextgeneration sequencing (NGS) studies have provided a complete profile of somatic mutations in CLL. [3][4][5][6][7][8][9] Few genes have mutations with mid/ low frequencies around 11% to 15%, whereas a larger group of genes are mutated at much lower frequencies (2%-5%), highlighting a striking interpatient heterogeneity. 10 The most commonly altered genes cluster in a limited number of pathways, including DNA damage response and cell cycle control, the nuclear factor-kB signaling pathway, messenger RNA processing, and NOTCH signaling among others.…”

Section: Introductionmentioning

confidence: 99%

Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia

Nadeu

Delgado

Royo

et al. 2016

291

328

Key Points• Clonal and subclonal mutations of NOTCH1 and TP53, clonal mutations of SF3B1, and ATM mutations in CLL have an impact on clinical outcome.• Clonal evolution in longitudinal samples occurs before and after treatment and may have an unfavorable impact on overall survival.Genomic studies have revealed the complex clonal heterogeneity of chronic lymphocytic leukemia (CLL). The acquisition and selection of genomic aberrations may be critical to understanding the progression of this disease. In this study, we have extensively characterized the mutational status of TP53, SF3B1, BIRC3, NOTCH1, and ATM in 406 untreated CLL cases by ultra-deep next-generation sequencing, which detected subclonal mutations down to 0.3% allele frequency. Clonal dynamics were examined in longitudinal samples of 48 CLL patients. We identified a high proportion of subclonal mutations, isolated or associated with clonal aberrations. TP53 mutations were present in 10.6% of patients (6.4% clonal, 4.2% subclonal), ATM mutations in 11.1% (7.8% clonal, 1.3% subclonal, 2% germ line mutations considered pathogenic), SF3B1 mutations in 12.6% (7.4% clonal, 5.2% subclonal), NOTCH1 mutations in 21.8% (14.2% clonal, 7.6% subclonal), and BIRC3 mutations in 4.2% (2% clonal, 2.2% subclonal). ATM mutations, clonal SF3B1, and both clonal and subclonal NOTCH1 mutations predicted for shorter time to first treatment irrespective of the immunoglobulin heavy-chain variable-region gene (IGHV) mutational status. Clonal and subclonal TP53 and clonal NOTCH1 mutations predicted for shorter overall survival together with the IGHV mutational status. Clonal evolution in longitudinal samples mainly occurred in cases with mutations in the initial samples and was observed not only after chemotherapy but also in untreated patients. These findings suggest that the characterization of the subclonal architecture and its dynamics in the evolution of the disease may be relevant for the management of CLL patients. (Blood. 2016;127(17):2122-2130