The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome
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The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome. / Brieghel, Christian; da Cunha-Bang, Caspar; Yde, Christina Westmose; Schmidt, Ane Yde; Kinalis, Savvas; Nadeu, Ferran; Andersen, Michael Asger; Jacobsen, Line Offenbach; Andersen, Mette Klarskov; Pedersen, Lone Bredo; Delgado, Julio; Baumann, Tycho; Mattsson, Mattias; Mansouri, Larry; Rosenquist, Richard; Campo, Elias; Nielsen, Finn Cilius; Niemann, Carsten Utoft.
In: Clinical Cancer Research, Vol. 26, No. 6, 15.03.2020, p. 1507-1515.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome
AU - Brieghel, Christian
AU - da Cunha-Bang, Caspar
AU - Yde, Christina Westmose
AU - Schmidt, Ane Yde
AU - Kinalis, Savvas
AU - Nadeu, Ferran
AU - Andersen, Michael Asger
AU - Jacobsen, Line Offenbach
AU - Andersen, Mette Klarskov
AU - Pedersen, Lone Bredo
AU - Delgado, Julio
AU - Baumann, Tycho
AU - Mattsson, Mattias
AU - Mansouri, Larry
AU - Rosenquist, Richard
AU - Campo, Elias
AU - Nielsen, Finn Cilius
AU - Niemann, Carsten Utoft
N1 - ©2020 American Association for Cancer Research.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - 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 the 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 the 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 refines 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.
AB - 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 the 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 the 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 refines 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.
U2 - 10.1158/1078-0432.CCR-18-4158
DO - 10.1158/1078-0432.CCR-18-4158
M3 - Journal article
C2 - 31919133
VL - 26
SP - 1507
EP - 1515
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 6
ER -
ID: 251998366