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Deep targeted sequencing of TP53 in chronic lymphocytic leukemia: clinical impact at diagnosis and at time of treatment

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@article{956ade8e7cab47cb95a01688d7f946f8,
title = "Deep targeted sequencing of TP53 in chronic lymphocytic leukemia: clinical impact at diagnosis and at time of treatment",
abstract = "In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoimmunotherapy. Patients harboring low burden TP53 mutations with variant allele frequencies of 0.3-15{\%} have been shown to have similar dismal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted Next Generation Sequencing assay allowing for the detection of TP53 mutations as low as 0.2{\%} variant allele frequency. Within a consecutive, single center cohort of 290 newly diagnosed patients with chronic lymphocytic leukemia, deletion of chromosome 17p was the only TP53 aberration significantly associated with shorter overall survival and treatment-free survival. We were unable to demonstrate any impact of TP53 mutations, whether high burden (variant allele frequency >10{\%}) or low burden (variant allele frequency ≤10{\%}), in the absence of deletion of chromosome 17p. In addition, the impact of high burden TP53 aberration (deletion of chromosome 17p and/or TP53 mutation with variant allele frequency >10{\%}) was only evident for patients with IGHV unmutated status; no impact of TP53 aberrations on outcome was seen for patients with IGHV mutated status. In 61 patients at time of treatment, the prognostic impact of TP53 mutations above 1{\%} variant allele frequency could be confirmed. This study furthers the identification of a clinical significant limit of detection for robust TP53 mutation analysis in chronic lymphocytic leukemia. Multicenter studies are needed for validation of ultra-sensitive TP53 mutation assays in order to define and implement a technical as well as clinical lower limit of detection.",
author = "Christian Brieghel and Savvas Kinalis and Yde, {Christina W} and Schmidt, {Ane Y} and Lars J{\o}nson and Andersen, {Michael A} and {da Cunha-Bang}, Caspar and Pedersen, {Lone B} and Geisler, {Christian H} and Nielsen, {Finn C} and Niemann, {Carsten U}",
note = "Copyright {\circledC} 2018, Ferrata Storti Foundation.",
year = "2019",
doi = "10.3324/haematol.2018.195818",
language = "English",
pages = "e--pub",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Fondazione/Ferrata Storti",

}

RIS

TY - JOUR

T1 - Deep targeted sequencing of TP53 in chronic lymphocytic leukemia

T2 - clinical impact at diagnosis and at time of treatment

AU - Brieghel, Christian

AU - Kinalis, Savvas

AU - Yde, Christina W

AU - Schmidt, Ane Y

AU - Jønson, Lars

AU - Andersen, Michael A

AU - da Cunha-Bang, Caspar

AU - Pedersen, Lone B

AU - Geisler, Christian H

AU - Nielsen, Finn C

AU - Niemann, Carsten U

N1 - Copyright © 2018, Ferrata Storti Foundation.

PY - 2019

Y1 - 2019

N2 - In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoimmunotherapy. Patients harboring low burden TP53 mutations with variant allele frequencies of 0.3-15% have been shown to have similar dismal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted Next Generation Sequencing assay allowing for the detection of TP53 mutations as low as 0.2% variant allele frequency. Within a consecutive, single center cohort of 290 newly diagnosed patients with chronic lymphocytic leukemia, deletion of chromosome 17p was the only TP53 aberration significantly associated with shorter overall survival and treatment-free survival. We were unable to demonstrate any impact of TP53 mutations, whether high burden (variant allele frequency >10%) or low burden (variant allele frequency ≤10%), in the absence of deletion of chromosome 17p. In addition, the impact of high burden TP53 aberration (deletion of chromosome 17p and/or TP53 mutation with variant allele frequency >10%) was only evident for patients with IGHV unmutated status; no impact of TP53 aberrations on outcome was seen for patients with IGHV mutated status. In 61 patients at time of treatment, the prognostic impact of TP53 mutations above 1% variant allele frequency could be confirmed. This study furthers the identification of a clinical significant limit of detection for robust TP53 mutation analysis in chronic lymphocytic leukemia. Multicenter studies are needed for validation of ultra-sensitive TP53 mutation assays in order to define and implement a technical as well as clinical lower limit of detection.

AB - In chronic lymphocytic leukemia, TP53 mutations and deletion of chromosome 17p are well-characterized biomarkers associated with poor progression-free and overall survival following chemoimmunotherapy. Patients harboring low burden TP53 mutations with variant allele frequencies of 0.3-15% have been shown to have similar dismal outcome as those with high burden mutations. We here describe a highly sensitive deep targeted Next Generation Sequencing assay allowing for the detection of TP53 mutations as low as 0.2% variant allele frequency. Within a consecutive, single center cohort of 290 newly diagnosed patients with chronic lymphocytic leukemia, deletion of chromosome 17p was the only TP53 aberration significantly associated with shorter overall survival and treatment-free survival. We were unable to demonstrate any impact of TP53 mutations, whether high burden (variant allele frequency >10%) or low burden (variant allele frequency ≤10%), in the absence of deletion of chromosome 17p. In addition, the impact of high burden TP53 aberration (deletion of chromosome 17p and/or TP53 mutation with variant allele frequency >10%) was only evident for patients with IGHV unmutated status; no impact of TP53 aberrations on outcome was seen for patients with IGHV mutated status. In 61 patients at time of treatment, the prognostic impact of TP53 mutations above 1% variant allele frequency could be confirmed. This study furthers the identification of a clinical significant limit of detection for robust TP53 mutation analysis in chronic lymphocytic leukemia. Multicenter studies are needed for validation of ultra-sensitive TP53 mutation assays in order to define and implement a technical as well as clinical lower limit of detection.

U2 - 10.3324/haematol.2018.195818

DO - 10.3324/haematol.2018.195818

M3 - Journal article

SP - e-pub

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -

ID: 56547339