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Clin Cancer Res. 2020 Jan 9. pii: clincanres.4158.2018. doi: 10.1158/1078-0432.CCR-18-4158. [Epub ahead of print]

The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome.

Author information

1
Department of Hematology, Copenhagen University Hospital.
2
Center for Genomic Medicine, Copenhagen University Hospital.
3
Centre for Genomic Medicine, Copenhagen University Hospital.
4
Lymphoid Neoplasms Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC).
5
Department of Clinical Genetics, Copenhagen University Hospital.
6
Dept. of Hematology, Hospital Clinic.
7
Department of Immunology, Genetics and Pathology; Department of Hematology, Uppsala University; Uppsala University Hospital.
8
Department of Molecular Medicine and Surgery, Karolinska Institute.
9
Hematopathology Section, Hospital Clinic, IDIBAPS, University of Barcelona.
10
Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet.
11
Department of Hematology, Rigshospitalet carsten.utoft.niemann@regionh.dk.

Abstract

PURPOSE:

Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at time of diagnosis remains unclear.

EXPERIMENTAL DESIGN:

We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing.

RESULTS:

Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refine prognostication in CLL; in particular for CLL-IPI low and intermediate risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways.

CONCLUSIONS:

We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

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