B3: Genes within the 3q26-29 amplicon present novel therapeutic candidates for oral cancer

Matthew Davidson1,Lynn McGarry1,Daniel James1,Emma Shanks1

1Cancer Research UK Beatson Institute, Glasgow, UK

Presenting date: Tuesday 3 November
Presenting time: 12.20-13.10

Background

Oral squamous cell carcinoma (OSCC) survival rates remain extremely low and, with a concurrent 300% increase in incidence over the past 20 years, new therapeutic intervention strategies are urgently required.
Amplification of the chromosomal region 3q26-29 has been identified in SCCs [1]. Individual genes within this region have been identified as oncogenic drivers and mediators of motility and invasion [2], but a global analysis of the genes encoded within 3q26-29 has not been conducted.

Method

We present a comprehensive analysis of the 3q26-29 amplicon, supported by transcriptomic data from The Cancer Genome Atlas (TCGA, n=498), experimental screening data, pathway analysis and mechanistic evaluation.

Results

Alterations in copy number within 3q26-29 are recapitulated at the gene expression level with enrichment at 3q29, 3q28 and 3q27.1. A 22-gene core network, containing known oncogenic drivers, was identified. Experimentally reduced expression of highly expressed genes identified 14 candidates which resulted in lethality of an OSCC cell line (29%<76%), 3 of which had a significantly lower survival rate (p<0.01, TCGA).
Furthermore, we identified 24 genes with increased gene expression under hypoxic conditions (0.1% O2, a poor prognostic indicator), including TP63, FXR1, SENP2 and EIF4A2. Two genes where reduced GE resulted in lethality (42%, 52%) had a significantly lower survival rate (p<0.01, TCGA), and were prioritised for target validation studies.

Conclusion

Genes encoded within 3q26-29 are frequently amplified in HNSCC, which is reflected at the expression level. Reduction of gene expression results in lethality of aggressive OSCCs, supporting selection as a therapeutic candidate. Further mechanistic analysis to support target validation will be discussed.