title: High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome.
abstract: Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in ≥1% of bone marrow cells was highly predictive of a TP53 gene mutation (P<0.0001) and was strongly associated with a high-risk karyotype (P<0.0001). The presence of ≥1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of ≥1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, P<0.0001) and 3.156 (CI: 1.502-6.628, P=0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Arjen H G
authors.initials: AH
authors.lastname: Cleven
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nardi
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chi Young
authors.initials: CY
authors.lastname: Ok
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Maitrayee
authors.initials: M
authors.lastname: Goswami
authors.affiliation: Center of Advanced Molecular Diagnostics, Brigham & Women's Hospital, Boston, MA, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Dal Cin
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Myrurgia A
authors.initials: MA
authors.lastname: Abdul Hamid
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sa A
authors.initials: SA
authors.lastname: Wang
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hasserjian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53