DiscussionThe survival rates of patients diagnosed with frequently presenting cancer types have improved dramatically in recent years, yet some cancers have not yet profited from such advances. 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 across multiple cancer types, with pronounced incidence in SCCs, including lung (). Individual genes within this region have been previously been identified as candidate drivers and mediators of motility and invasion, which are associated with a poor patient outcome . However, a global analysis of the genes contained within 3q26-29 has not been conducted.
We present a comprehensive, multi-parametric analysis of the 3q26-29 region, supported by transcriptomic data from The Cancer Genome Atlas (TCGA, n=498). Of the genes located within 3q26-29, 188 had available copy number variation (CNV) and gene expression (GE) data (TCGA). A total of 62% of genes demonstrated increased GE (Z score ≥2) in more than 10% of the patient population, demonstrating large alterations in copy number are translated at the gene expression level. Mapping of these genes on to the inter-chromosomal regions identified an enrichment of genes in locations 3q29, 3q28 and 3q27.1. Amplification of 3q26-29 has substantial functional implications, exemplified through identification of a 22 gene-core network containing known oncogenic drivers including TP63, SOX2, SENP2/SUMO1 (Metacore) .
The potential of genes within 3q26-29 as candidates for therapeutic intervention was assessed. Reduced expression of a subset of genes (siRNA) which are highly expressed in both transcriptomic data and GE data from an experimental OSCC cell line (T3N2b, ‘Liv7k’ with 3q26-29 CNV amplification) identified 14 genes which resulted in cell lethality (29%<76%). Associated survival data (p<0.01, TCGA) supported further prioritisation of 3 genes: PSMD2, IGF2BP2 and NDUFB5.
The presence of intra-tumoural regions of hypoxia is also associated with a poor prognosis. We identified 24 genes with increased GE under hypoxic conditions (1% O2), including TP63, FXR1, SENP2, SENP5 and EIF4A2. Two genes with a significantly lower survival rate (YEATS2 and IL1RAP, p<0.01) were prioritised. Mechanistic studies to support target validation for drug development are underway and will be discussed.
1. Wang, J., et al., Integrative Genomics Analysis Identifies Candidate Drivers at 3q26-29 Amplicon in Squamous Cell Carcinoma of the Lung. Clinical Cancer Research, 2013. 19(20): p. 5580-5590.
2. Kelley, L., S. Shahab, and S. Weed, Actin cytoskeletal mediators of motility and invasion amplified and overexpressed in head and neck cancer. Clinical & Experimental Metastasis, 2008. 25(4): p. 289-304.