The prognostic significance of MET overexpression in head and neck squamous cell carcinomas


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Stephanie Craig1,Victoria Bingham1,Stephen McQuaid1,Lesley Anderson1,Michael Moran1,Manuel Salto-Tellez1,Simon McDade1,Jacqueline James1
1Queens University Belfast

Abstract

Background

Increased expression and/or amplification of the p53 family member p63 is observed in the majority of HNSCC and plays essential p53-independent roles in promoting and maintaining squamous transformation. Integration of results from genome-wide ChIP-Seq experiments investigating the p53/p63 axis with gene expression profiling of HNSCC identified the receptor tyrosine kinase MET as a potential p63 target gene. MET is overexpressed in 80% of HNSCC and has been associated with poor prognosis in SCC but not necessarily HNSCC. This study investigates the prognostic value of MET overexpression in HNSCC with consideration to HPV status through the use of integrative analyses.

Method

Staining of TMAs by c-MET immunohistochemistry and MET in situ hybridisation by RNAScope. Subsequent image analysis by manual and automated (SpotStudio Software) scoring. HNSCC validation data was derived from TCGA RNA-Seq data. Results were collated, processed and modelled in R using the car, survival, pROC and base packages.

Results

Investigation in TMAs from a cohort of 191 HNSCC patient samples revealed that MET mRNA and protein expression is strongly correlated and significantly elevated in the HPV negative’s compared to the HPV positive cases, irrespective of scoring metric utilised. Furthermore when these HPV subpopulations are dichotomised by high and low expression based on ROC curve analysis, high MET was found to correlate with significantly worse prognosis and relapse in the HPV negative but not HPV positive sub-populations. Multivariate analysis confirmed these findings are independent of other clinicopathological features available for these patients. These findings were validated in an independent, publically available mRNA dataset.

Conclusion

MET is overexpressed in HNSCC and correlates with poor prognosis and relapse in HPV negative cases. Further investigation of this sub-population is warranted as MET overexpression has been previously associated with therapeutic resistance and may benefit from the addition of MET inhibitors to treatment.

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