Abstract
BackgroundOral Squamous Cell Carcinoma (OSCC) is a major cause of cancer death worldwide, which is mainly due to recurrence leading to treatment failure and patient death. Histological status of surgical margins is a currently available assessment for recurrence risk in OSCC; however histological status does not predict recurrence, even in patients with histologically negative margins. Therefore, molecular analysis of histologically normal resection margins and the corresponding OSCC may aid in identifying a gene signature predictive of recurrence.MethodsWe used a meta-analysis of 199 samples (OSCCs and normal oral tissues) from five public microarray datasets, in addition to our microarray analysis of 96 OSCCs and histologically normal margins from 24 patients, to train a gene signature for recurrence. Validation was performed by quantitative real-time PCR using 136 samples from an independent cohort of 30 patients.ResultsWe identified 138 significantly over-expressed genes (> 2-fold, false discovery rate of 0.01) in OSCC. By penalized likelihood Cox regression, we identified a 4-gene signature with prognostic value for recurrence in our training set. This signature comprised the invasion-related genes MMP1, COL4A1, P4HA2, and THBS2. Over-expression of this 4-gene signature in histologically normal margins was associated with recurrence in our training cohort (p = 0.0003, logrank test) and in our independent validation cohort (p = 0.04, HR = 6.8, logrank test).ConclusionGene expression alterations occur in histologically normal margins in OSCC. Over-expression of the 4-gene signature in histologically normal surgical margins was validated and highly predictive of recurrence in an independent patient cohort. Our findings may be applied to develop a molecular test, which would be clinically useful to help predict which patients are at a higher risk of local recurrence.
Highlights
Oral Squamous Cell Carcinoma (OSCC) is a major cause of cancer death worldwide, which is mainly due to recurrence leading to treatment failure and patient death
One probable reason for this deficit is that the application of strict inclusion criteria, presents a challenge for obtaining adequate sample size to develop a prognostic signature that can predict recurrence in oral carcinoma. We addressed this challenge through a hypothesis-driven approach, based on the hypothesis that commonly over-expressed genes in OSCC and a subset of histologically normal margins are biomarkers of recurrence
Meta-analysis of published microarray studies Our goal was to identify a prognostic signature for recurrence in OSCC, based on the hypothesis that gene expression deregulation occurring in OSCC would be an
Summary
Oral Squamous Cell Carcinoma (OSCC) is a major cause of cancer death worldwide, which is mainly due to recurrence leading to treatment failure and patient death. Oral Squamous Cell Carcinoma (OSCC) accounts for 24% of all head and neck cancers [1]. Candidate-gene approach studies have identified genetic alterations in surgical resection margins in head and neck squamous cell carcinoma (HNSCC) from different disease sites, e.g., oral cavity, pharynx/hypopharynx, larynx [6,7,8,9,10,11,12,13,14,15,16]. Promoter hypermethylation of CDKN2A, CCNAI and DCC was associated with decreased time to head and neck cancer recurrence [10]
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