Abstract
Ultra-deep targeted sequencing (UDT-Seq) has advanced our knowledge on the incidence and functional significance of somatic mutations. However, the utility of UDT-Seq in detecting copy number alterations (CNAs) remains unclear. With the goal of improving molecular prognostication and identifying new therapeutic targets, we designed this study to assess whether UDT-Seq may be useful for detecting CNA in oral cavity squamous cell carcinoma (OSCC). We sequenced a panel of clinically actionable cancer mutations in 310 formalin-fixed paraffin-embedded OSCC specimens. A linear model was developed to overcome uneven coverage across target regions and multiple samples. The 5-year rates of secondary primary tumors, local recurrence, neck recurrence, distant metastases, and survival served as the outcome measures. We confirmed the prognostic significance of the CNA signatures in an independent sample of 105 primary OSCC specimens. The CNA burden across 10 targeted genes was found to predict prognosis in two independent cohorts. FGFR1 and PIK3CAamplifications were associated with prognosis independent of clinical risk factors. Genes exhibiting CNA were clustered in the proteoglycan metabolism, the FOXO signaling, and the PI3K-AKT signaling pathways, for which targeted drugs are already available or currently under development. UDT-Seq is clinically useful to identify CNA, which significantly improve the prognostic information provided by traditional clinicopathological risk factors in OSCC patients.
Highlights
Oral cavity squamous cell carcinoma (OSCC) is a leading cause of morbidity and mortality
Ultra-deep targeted sequencing (UDT-Seq) is clinically useful to identify copy number alterations (CNAs), which significantly improve the prognostic information provided by traditional clinicopathological risk factors in oral cavity squamous cell carcinoma (OSCC) patients
We extend the conventional utility of UDT-Seq in single nucleotide variants (SNVs) detection and demonstrate that high-depth UDTSeq is clinically useful for identifying CNA
Summary
Oral cavity squamous cell carcinoma (OSCC) is a leading cause of morbidity and mortality. Previous studies have shown that CNAs can predict prognosis in solid malignancies [5, 8, 10,11,12], the clinical significance of CNAs in OSCC remains unclear and requires thorough investigation in large clinical cohorts [9]. In this scenario, determining how CNA contributes to clinical outcomes in patients with OSCC is a critical question and technical improvements in genomic methods are crucial to answering it. With the goal of improving molecular prognostication and identifying new therapeutic targets, we designed this study to assess whether UDT-Seq may be useful for detecting CNA in oral cavity squamous cell carcinoma (OSCC)
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