Abstract 5246: Genomic determinants of aggressive phenotype in oral SCC

Abstract

Abstract Background: Oral squamous cell carcinoma (OSCC), the common form of HNSCC, affects over 600,000 cases worldwide per annum. We reviewed 561 consecutive cases in Liverpool1 finding that the most predictive marker for death was extra-capsular spread (ECS) from cervical lymph nodes (p<0.001). Overall survival at 5 years was 56% for all 561 cases, but only 24% in the ECS group independently of its site, extent or the stage of the primary tumour2. The presence of ECS predicted for recurrence, usually at the primary site, even when surgical margins were generous indicating that this aggressive phenotype is likely to be expressed in the primary tumour as much as in the metastatic cells. Hypothesis: We hypothesised that molecular pathways represented by global gene expression signatures would be detected in the samples associated with ECS. Methods: High density exon array expression analysis was performed on fresh frozen samples comprising T2 and T4 stage OSCC cases having no nodal involvement; positive nodes without ECS or positive nodes plus ECS picked longitudinally from a single centre series (n>200) with bias towards increasing the numbers with ECS. Contingency tests were performed to assess the significance of ECS associated pathways. Results and Discussion: Power analysis showed that 90% of all ≥ twofold differences in gene expression between node negative & ECS cases were significant. Affected pathways included: keratinocyte differentiation, ECM remodelling, chemokines & adhesion, TGF & WNT: cytoskeletal remodelling, regulation of actin cytoskeleton by rho GTPases & cell adhesion/ histamine H1 receptor signalling/loss of cell barrier (p values:7.7×10−15 – 1.9×10−6). A 29 gene signature able to discriminate the ECS from the non-ECS cases with 78% sensitivity and 86% specificity was found. Blocked differentiation of keratinocytes at an early (“stem cell”/ EMT) stage was suggested by the genes which included keratin 15, keratinocyte differentiation-associated protein, retinol binding protein 1, cellular serine peptidase inhibitor (Kazal type 6), and stratifin implicated in mesenchymal stem cells, basal, suprabasal expression and keratinocyte activation and differentiation. The signature may be connected with these tumours having poor prognosis. Conclusion: This is a significant and novel finding suggesting that the pattern of metastasis in regional lymph nodes can be predicted by molecular pathways prevalent in a small oral biopsy. 1. Rogers et al. Oral Oncol 2009;45(3):201-211 2. Shaw et.al. Head Neck 2010;32(6):714-722 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5246. doi:10.1158/1538-7445.AM2011-5246