title: Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes.
abstract: Although next-generation sequencing has allowed for the detection of somatic mutations in myelodysplastic syndromes (MDS), the clinical relevance of variant allele frequency (VAF) for the majority of mutations is unknown. We profiled TP53 and 20 additional genes in our training set of 219 patients with MDS or secondary acute myeloid leukemia with findings confirmed in a validation cohort. When parsed by VAF, TP53 VAF predicted for complex cytogenetics in both the training (P=0.001) and validation set (P<0.0001). MDS patients with a TP53 VAF > 40% had a median overall survival (OS) of 124 days versus an OS that was not reached in patients with VAF <20% (hazard ratio (HR), 3.52; P=0.01) with validation in an independent cohort (HR, 4.94, P=0.01). TP53 VAF further stratified distinct prognostic groups independent of clinical prognostic scoring systems (P=0.0005). In multivariate analysis, only a TP53 VAF >40% was an independent covariate (HR, 1.61; P<0.0001). In addition, SRSF2 VAF predicted for monocytosis (P=0.003), RUNX1 VAF with thrombocytopenia (P=0.01) and SF3B1 with ringed sideroblasts (P=0.001). Together, our study indicates that VAF should be incorporated in patient management and risk stratification in MDS.
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Sallman
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Komrokji
authors.affiliation: Genoptix, Inc., a Novartis company, Carlsbad, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Vaupel
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.|Hematology Department, CHU of Nice, Nice, France.|Faculty of Medicine, University Nice Sophia Antipolis, Nice, France.|Mediterranean Center of Molecular Medicine, INSERM U1065, Nice, France.|French Group of Myelodysplasia, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Cluzeau
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, FL, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Geyer
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: McGraw
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Al Ali
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lancet
authors.affiliation: Genoptix, Inc., a Novartis company, Carlsbad, CA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: McGinniss
authors.affiliation: Genoptix, Inc., a Novartis company, Carlsbad, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nahas
authors.affiliation: King's College London School of Medicine, Department of Haematological Medicine, Rayne Institute, King's College London School of Medicine, London, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Smith
authors.affiliation: King's College London School of Medicine, Department of Haematological Medicine, Rayne Institute, King's College London School of Medicine, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kulasekararaj
authors.affiliation: King's College London School of Medicine, Department of Haematological Medicine, Rayne Institute, King's College London School of Medicine, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Mufti
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: List
authors.affiliation: Genoptix, Inc., a Novartis company, Carlsbad, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hall
authors.affiliation: Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Padron
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D020732:Cytogenetic Analysis; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; C493728:RUNX1 protein, human; D017413:Ribonucleoprotein, U2 Small Nuclear; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors