Gene Expression Analysis As a Tool in Early-Stage Oral Cancer Management
[Show abstract] [Hide abstract] ABSTRACT: Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.
- "In particular, with its relation to outcome following chemoradiation (Fig. 4, right) and its joint relation with HPV status to outcome (Fig. 6, left), MATH should be useful in clinical trials on de-intensification of organ-preservation therapy for oropharyngeal cancer, in which chemoradiation is a standard of care and HPV status is already considered in trial design  . In HPV-negative HNSCC, the relation of MATH to nodal involvement suggests that MATH might assist clinical studies in evaluating the need for cervical node dissection in patients with low-T/cN0 oral cancer, a decision presently based on tumor depth and sentinel node mapping . Furthermore, MATH adds usefully to TNM staging in prognosticating overall survival of patients having either oral-cavity or laryngeal tumors (Fig. 7 ). "
[Show abstract] [Hide abstract] ABSTRACT: Background: Extracapsular spread (ECS) in cervical lymph nodes is the single-most prognostic clinical variable in oral squamous cell carcinoma (OSCC), but diagnosis is possible only after histopathological examination. A promising biomarker in the primary tumour, alpha smooth muscle actin (SMA) has been shown to be highly prognostic, however, validated biomarkers to predict ECS prior to primary treatment are not yet available. Methods: In 102 OSCC cases, conventional imaging was compared with pTNM staging. SERPINE1, identified from expression microarray of primary tumours as a potential biomarker for ECS, was validated through mRNA expression, and by immunohistochemistry (IHC) on a tissue microarray from the same cohort. Similarly, expression of SMA was also compared with its association with ECS and survival. Expression was analysed separately in the tumour centre and advancing front; and prognostic capability determined using Kaplan-Meier survival analysis. Results: Immunohistochemistry indicated that both SERPINE1 and SMA expression at the tumour-advancing front were significantly associated with ECS (P<0.001). ECS was associated with expression of either or both proteins in all cases. SMA+/SERPINE1+ expression in combination was highly significantly associated with poor survival (P<0.001). MRI showed poor sensitivity for detection of nodal metastasis (56%) and ECS (7%). Both separately, and in combination, SERPINE1 and SMA were superior to MRI for the detection of ECS (sensitivity: SERPINE1: 95%; SMA: 82%; combination: 81%). Conclusion: A combination of SMA and SERPINE1 IHC offer potential as prognostic biomarkers in OSCC. Our findings suggest that biomarkers at the invasive front are likely to be necessary in prediction of ECS or in therapeutic stratification.
- "In a recent meta-analysis of over 60 studies of differential gene-expression profiling in HNSCC, one study of a limited number of cases predicted ECS by geneexpression analysis from primary site tissue (Zhou et al, 2006; Yu et al, 2008). It is also evident from many studies that there is a high risk for false discovery, and careful validation is mandated before establishing clinical biomarkers (Mroz and Rocco, 2012; van Hooff et al, 2012a). Our sampling of tissue for gene-expression analysis was superficial, which may be criticised by excluding the more informative tumour-advancing front. "
- [Show abstract] [Hide abstract] ABSTRACT: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature and we assessed its representation in 4 independent human datasets comprising 324 patients using weighted voting and Gene Set Enrichment Analysis (GSEA). Kaplan-Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A qRT-PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy. NGS revealed conservation of human driver pathway mutations in mouse OSCC including in Trp53, MAPK, PI3K, NOTCH, JAK/STAT and FAT1-4. Moreover, comparative analysis between The Cancer Genome Atlas (TCGA) and mouse samples defined AKAP9, MED12L and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in 4 independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified OSCC patients with a 93.5% accuracy. These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer.
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