Non-coding recurrent mutations in chronic lymphocytic leukaemia

Abstract

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: The case of subset #2

“…Therefore, differences in the number of subset #2 cases included, may also account for the observed inconsistencies between the 2 studies. Nevertheless, our data indeed support that subset #2 cases are a member of the i-CLL group, 21 which is in line with the intermediate IGHV mutational status observed both in subset #2 cases and non-subset #2 cases, 20 and provides evidence that the i-CLL group corresponds to a 'true' group and not merely a mix of 'left-over' cases. Hence, according to the methylation profiles, it can be speculated that the i-CLL group might have a different ontogenetic derivation compared to the other subgroups, which is also reflected by their borderline somatic hypermutation levels.…”

“…These latter patients are particularly interesting since they display poor clinical outcome despite mainly carrying mutated IGHV genes and were recently suggested, though based on few cases, to have an intermediate epigenetic signature. [18][19][20][21] Using pyrosequencing, we could confirm the clinical utility of the proposed epigenetic model, as it remained as an independent factor predicting both overall survival (OS) and time-to-first-treatment (TTFT), even in the presence of the IGHV gene mutational status. In addition, we observed that almost all subset #2 cases displayed a methylation signature similar to the i-CLL group, hence supporting the actual existence of a third epigenetic subgroup.…”

NOTCH1 mutational status in chronic lymphocytic leukaemia: clinical relevance of subclonal mutations and mutation types

“…Clinically, patients with NOTCH1 mutations (NOTCH1-mut) experienced a significantly shorter TTFT than NOTCH1-wt cases (median TTFT: 31 months vs. 85 months, P < 0Á0001; Fig 1C), and a similar trend was observed for OS (median OS: 175 months vs. not reached months, P < 0Á0001; Fig 1D), in agreement with previous studies (Puente et al, 2011(Puente et al, , 2015. Moreover, NOTCH1 mutations were more frequent in tris12 CLL cases and IGHV unmutated cases (P < 0Á0001 and P < 0Á0001; Fig 1E, F).…”

Barcelona conference on epigenetics and cancer 2016 – beyond cancer genomes

“…The evaluation of the genomic landscape of 452 CLL cases and 54 patients with a monoclonal increase in B cells identified 60 driver mutations, some of them being recurrent, such as NOTCH1 mutations. 40 The CLL consortium identified novel recurrent mutations in noncoding regions, including the 3 0 UTR region of NOTCH1 causing aberrant splicing events correlating with a more aggressive disease; mutations in an enhancer of the B cell-specific transcription factor PAX5 correlating with reduced expression of the gene. The current efforts of his team are focused on analyzing the role of driver mutations in genes such as MYD88 and CHD2 in creating a tumor-promoting inflammatory microenvironment, and modulating chromatin organization.…”