Abstract
Simple SummaryA comprehensive analysis based on mutational signatures and oncogenic signaling pathways to identify a specific subgroup of patients that had a significantly negative impact on both disease-free and overall survival in oral cavity squamous cell carcinoma (OCSCC) from whole exome-sequencing data. This analysis has revealed a variety of biologically relevant candidate target genes. Thirty percent of 165 tumors had multiple targetable alterations in multiple pathways. This suggests the complex interplay and crosstalk of oncogenic signaling pathways play an important role on the outcome of patients with OCSCC, and the candidate genes and pathways identified may include prognostic genetic biomarkers or therapeutic targets for OCSCC.Mutational profiling of patients’ tumors has suggested that the development of oral cavity squamous cell carcinoma (OCSCC) is driven by multiple genes in multiple pathways. This study aimed to examine the association between genomic alterations and clinical outcomes in patients with advanced stages OCSCC to facilitate prognostic stratification. We re-analyzed our previous whole-exome sequencing data from 165 long-term follow-ups of stages III and IV patients with OCSCC. Their frequent mutations were mapped to 10 oncogenic signaling pathways. Clinicopathological risk factors, relapse, and survival were analyzed to identify the genetic factors associated with advanced OCSCC. Frequent genetic alterations included point mutations in TP53, FAT1, NOTCH1, CASP8, CDKN2A, HRAS, PIK3CA, KMT2B (also known as MLL4), and LINC00273; amplified segments in CCND1, EGFR, CTTN, and FGFR1; and lost segments in CDKN2A, ADAM3A, and CFHR1/CFHR4. Comprehensive analysis of genetic alterations revealed that subgroups based on mutational signatures had a significant negative impact on disease-free survival (p = 0.0005) and overall survival (p = 0.0024). Several important signaling pathways were identified to be frequently genetically altered in our cohort. A specific subgroup of patients with alterations in NOTCH, RTK/RAS/MAPK, and TGF-beta pathways that had a significantly negative impact on disease-free survival (p = 0.0009). Thirty percent of samples had multiple targetable mutations in multiple pathways, indicating opportunities for novel therapy.
Highlights
Oral cavity squamous cell carcinoma (OCSCC) is the most common subtype of head and neck cancer worldwide [1]
One hundred and sixty-five paired fresh-frozen malignant and adjacent non-malignant tissue specimens from treatment-naïve patients with resected oral cavity squamous cell carcinoma (OCSCC) were analyzed for genetic alterations by using the whole-exome sequencing (WES) approach
We found that 61.36% of all mutations in CCND1 occurred in combination with a second oncogenic mutation, and that oncogenic mutations in the HRAS gene often occur in combination with a mutation in the RICTOR gene (3/12, 25%)
Summary
Oral cavity squamous cell carcinoma (OCSCC) is the most common subtype of head and neck cancer worldwide [1]. Recent advances in next-generation sequencing (NGS) of head and neck squamous cell carcinoma (HNSCC) samples of different etiologies have revealed that HNSCC development is mainly driven by loss-of-function alterations, including gene mutations in TP53, CDKN2A, HRAS, PIK3CA, BRAF, CASP8, and NOTCH1 [5,6,7,8,9]. Another genomic analysis of OCSCC revealed five driver pathways (Notch, P53, cell cycle, Wnt, and mitogenic signaling) and defined novel molecular subtypes of OCSCC, characterized by frequent CASP8 mutations accompanied by copy-number alterations [8,10]
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