To address these issues, we conducted a cytogenetic study of a large series of untreated symptomatic patients enrolled in a prospective, randomized, open-label clinical trial. The WM1 study took place in 101 centers in five countries and enrolled 339 patients with WM, 37 patients with non-MALT marginal zone lymphoma (MZL), and 38 patients with lymphoplasmacytic lymphoma, who were all randomly assigned to receive chlorambucil or fludarabine. 7Here we report our cytogenetic findings in 174 of the WM patients enrolled in this trial.

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...

Interleukin-6 (IL-6) is known to promote tumour growth and survival. We evaluated IL-6 gene amplification in tumours from 53 glioma patients using fluorescence in situ hybridisation. Amplification events were detected only in glioblastomas (15 out of 36 cases), the most malignant tumours, and were significantly associated with decreased patient survival.

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Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.