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

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@article{ebd9e4c019c5472791962f51f7387bf9,
title = "The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome",
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.",
author = "Christian Brieghel and {da Cunha-Bang}, Caspar and Yde, {Christina Westmose} and Schmidt, {Ane Yde} and Savvas Kinalis and Ferran Nadeu and Andersen, {Michael Asger} and Jacobsen, {Line Offenbach} and Andersen, {Mette Klarskov} and Pedersen, {Lone Bredo} and Julio Delgado and Tycho Baumann and Mattias Mattsson and Larry Mansouri and Richard Rosenquist and Elias Campo and Nielsen, {Finn Cilius} and Niemann, {Carsten U}",
note = "Copyright {\circledC}2020, American Association for Cancer Research.",
year = "2020",
month = "3",
day = "15",
doi = "10.1158/1078-0432.CCR-18-4158",
language = "English",
volume = "26",
pages = "1507--1515",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",
number = "6",

}

RIS

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 U

N1 - Copyright ©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 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.

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 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.

U2 - 10.1158/1078-0432.CCR-18-4158

DO - 10.1158/1078-0432.CCR-18-4158

M3 - Journal article

VL - 26

SP - 1507

EP - 1515

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 6

ER -

ID: 59005280