The presence of Y674/Y675 phosphorylated NTRK1 via TP53 repression of PTPN6 expression as a potential prognostic marker in neuroblastoma.
Adolescent
Biomarkers, Tumor
Child
Child, Preschool
Disease-Free Survival
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Infant
Infant, Newborn
Neuroblastoma
/ metabolism
Phosphorylation
Prognosis
Protein Tyrosine Phosphatase, Non-Receptor Type 6
/ metabolism
Receptor, trkA
/ metabolism
Survival Rate
Tumor Suppressor Protein p53
/ metabolism
Childhood cancer
NTRK1
Neuroblastoma
PTPN6
TP53
Journal
Human pathology
ISSN: 1532-8392
Titre abrégé: Hum Pathol
Pays: United States
ID NLM: 9421547
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
01
06
2018
revised:
05
12
2018
accepted:
06
12
2018
pubmed:
31
12
2018
medline:
20
11
2019
entrez:
31
12
2018
Statut:
ppublish
Résumé
The tumor suppressor TP53 promotes nerve growth factor receptor (NTRK1) -Y674/Y675 phosphorylation (NTRK1-pY674/pY675) via repression of the NTRK1 phosphatase PTPN6 in a ligand-independent manner, resulting in suppression of breast cancer cell proliferation. Moreover, NTRK1-pY674/pY675 together with low levels of PTPN6 and TP53 expression is associated with favorable disease-free survival of breast cancer patients. We determined whether in neuroblastoma this protein expression pattern impacts relapse-free survival (RFS). NTRK1-pY674/pY675, PTPN6, and TP53 expression was assessed in 98 neuroblastoma samples by immunohistochemistry. Association between expression levels and RFS was investigated by multivariate and Kaplan-Meier analysis. Mutant or wild-type TP53 was identified by sequencing tumor DNA. Tumors expressing NTRK1-pY674/pY675 and low or undetectable levels of PTPN6 and TP53 were significantly associated with 5-year RFS (P = .014) when the dataset was stratified by MYCN amplification, segmental chromosomal abnormalities and histology. Similar results were observed with tumors expressing wild-type TP53, NTRK1-pY674/pY675 and low or undetectable levels of PTPN6. Kaplan-Meier analysis demonstrated a significant correlation (P = .004), with a 50% probability of RFS (median survival 4.73 years) when present compared with 19.51% (median survival 11.63 months) when absent. Similar results were seen with non-amplified MYCN or unfavorable/undifferentiating samples and tumors from patients aged 18 months or less. Importantly, NTRK1-pY674/pY675 is an independent predictor of improved RFS. These results strongly suggest that NTRK1-pY674/pY675 together with wild-type TP53 and undetectable or low levels of PTPN6 expression is a potential biomarker of improved RFS of neuroblastoma patients. The predictive value of NTRK1-pY674/pY675 together with wild-type TP53 and low PTPN6 expression could contribute to neuroblastoma patient prognosis.
Identifiants
pubmed: 30594749
pii: S0046-8177(18)30496-9
doi: 10.1016/j.humpath.2018.12.003
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
Tumor Suppressor Protein p53
0
Receptor, trkA
EC 2.7.10.1
PTPN6 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 6
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
182-192Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.