Targeted sequencing of cancer-related genes in nasopharyngeal carcinoma identifies mutations in the TGF-ß pathway.
Cancer Med
; 8(11): 5116-5127, 2019 Sep.
Article
en En
| MEDLINE
| ID: mdl-31328403
ABSTRACT
Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein-Barr virus (EBV). We envisioned that in-depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty-three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep-sequenced (>1000×) with respect to a panel of 409 cancer-related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF-κB, and TGF-ß pathways. In addition, patients harbored CNV among 409 cancer-related genes and missense mutations in TGF-ß/SMAD signaling were associated with poor overall survival and poor recurrence-free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD-dependent TGF-ß signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF-ß-mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF-ß signaling contributes to exacerbating the NPC pathogenesis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oncogenes
/
Transducción de Señal
/
Neoplasias Nasofaríngeas
/
Factor de Crecimiento Transformador beta
/
Carcinoma Nasofaríngeo
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Cancer Med
Año:
2019
Tipo del documento:
Article
País de afiliación:
China