Multi-Omics Profiling Identifies Novel Therapeutic Targets and Pathobiological Mechanisms in Oral Cancer

Area of Science:

• Genetics and Genomics
• Cancer Research
• Bioinformatics

Background:

• Oral cancer (OC) presents a significant therapeutic challenge with limited validated molecular targets.
• Identifying novel targets is crucial for developing effective oral cancer treatments.

Purpose of the Study:

• To identify and prioritize potential therapeutic targets for oral cancer using a multi-omics Mendelian randomization (MR) approach.
• To validate MR findings through experimental methods and assess potential drug safety implications.

Main Methods:

• Two-sample Mendelian randomization (MR) framework harmonizing cis-pQTL data with oral cancer GWAS meta-data.
• Robust validation including replication studies, colocalization, SMR, HEIDI tests, and eQTL analysis.
• Protein-protein interaction networks, pathway enrichment (KEGG/GO), mediation, druggability, and side effect analyses.
• Quantitative real-time PCR (qRT-PCR) to examine mRNA expression levels in oral cancer cell lines and normal cells.

Main Results:

• Multi-omics MR identified TNFSF8 as a Tier 1 target (p=2.49×10⁻⁸, OR=1.24), with XXYLT1 (p=1.41×10⁻⁴, OR=1.34) and HSD17B14 (p=0.04, OR=2.00) as Tier 2 targets.
• TNFSF8 eQTLs mediated 72.80% of risk via protein upregulation; XXYLT1 expression explained 24.65% of risk through elevated plasma protein levels.
• Mediation analyses linked CD4+ T cells to HSD17B14 upregulation and cigarette consumption/CD8+ T cells to TNFSF8 upregulation.
• qRT-PCR confirmed XXYLT1 and HSD17B14 upregulation in oral cancer cells; TNFSF8 was not detected, aligning with an immune-mediated mechanism.
• Systemic TNFSF8 inhibition may increase skin cancer risk.

Conclusions:

• Multi-omics MR effectively prioritizes TNFSF8 as a key therapeutic target for oral cancer.
• Experimental validation supports the dysregulation of XXYLT1 and HSD17B14, while TNFSF8's role appears immune-mediated.
• Further functional studies are warranted to elucidate the precise mechanisms and therapeutic potential of these targets.