Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

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‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/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‐β 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‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis.

Molecular landscape and subtype-specific therapeutic response of nasopharyngeal carcinoma revealed by integrative pharmacogenomics

“…2e ) 38 . Consistent conclusion was also demonstrated by previous report 39 . Among top frequent COSMIC signatures in NPC, signatures 2 and 13 were related to APOBEC family, signatures 6, 15, 20, and 16 were related to DNA mismatch repair, signature 5 was of unknown aetiology, signatures 4 and 29 were due to tobacco, and signature 1 was associated with methylcytosine (Supplementary Fig.…”

Targeting Epstein-Barr Virus in Nasopharyngeal Carcinoma

“…Although TPA alone can induce the lytic cycle in EBV-positive NPC cells in a cell-context-dependent manner, a combination of TPA and other HDACi may be needed to maximize the induction of EBV reactivation (25,104). As TPA is a classical tumor-promoting agent and can cause skin carcinogenesis (129), it is intrinsically unsuitable as a clinical drug. Nevertheless, other clinically approved PKC activators are worth exploring for their potential ability to induce the lytic cycle in NPC cells.…”

Germline Variants Associated with Nasopharyngeal Carcinoma Predisposition Identified through Whole-Exome Sequencing

“…Other JAK2 somatic mutations found in exon 12, R683 and T875, have also been linked to hematological malignancies [ 69 , 70 , 71 ]. Although little has been reported on JAK2 mutations in NPC, two research groups have identified amplifications in the JAK2 gene that are responsible for promoting cell proliferation and cell signalling in NPC [ 50 , 72 ]. Moreover, JAK2 has been found to be overexpressed in NPC tissues and high JAK2 expression correlates with poor clinical outcome [ 73 ].…”