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In Vivo CRISPR/Cas9 Screening to Simultaneously Evaluate Gene Function in Mouse Skin and Oral Cavity
Published on: November 2, 2020
Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers
Curtis R Pickering1, Jiexin Zhang, Suk Young Yoo
1Departments of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Abstract:
The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we conducted comprehensive genomic analysis of gene expression, copy number, methylation, and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, and TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of caspase-8 (CASP8) defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers.
Insights
Survival in oral squamous cell carcinoma (OSCC) remains poor, prompting genomic analysis for new targets. This study identified key driver pathways and targetable genes, offering hope for novel treatments in this head and neck cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Survival rates for oral squamous cell carcinoma (OSCC) have stagnated for decades.
- There is a critical need for novel molecular targets to improve patient outcomes.
Purpose of the Study:
- To conduct a comprehensive genomic analysis of OSCC.
- To identify driver pathways and key genes for potential therapeutic intervention.
Main Methods:
- Integrated analysis of gene expression, copy number, methylation, and point mutations in OSCC.
- Functional studies investigating the role of NOTCH1 signaling.
Main Results:
- Identified four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two key genes (FAT1, CASP8).
- The Notch pathway was defective in 66% of patients; functional NOTCH1 inhibited OSCC cell proliferation.
- Frequent caspase-8 (CASP8) mutation defines a new OSCC subtype.
- 80% of patients had alterations in targetable genes.
Conclusions:
- Genomic alterations in OSCC reveal potential therapeutic targets.
- Targetable genomic alterations in 80% of patients suggest new treatment possibilities for OSCC.
- Understanding these molecular drivers can inform future therapeutic strategies for oral cancer.
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