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Open Access Highly Accessed Research article

A gene signature in histologically normal surgical margins is predictive of oral carcinoma recurrence

Patricia P Reis12, Levi Waldron3, Bayardo Perez-Ordonez4, Melania Pintilie56, Natalie Naranjo Galloni17, Yali Xuan1, Nilva K Cervigne1, Giles C Warner8, Antti A Makitie9, Colleen Simpson10, David Goldstein10, Dale Brown10, Ralph Gilbert10, Patrick Gullane10, Jonathan Irish10, Igor Jurisica113* and Suzanne Kamel-Reid112134*

Author Affiliations

1 Div. of Applied Molecular Oncology, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

2 Dept. of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University - UNESP, Botucatu, SP, Brazil

3 Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Toronto, ON, Canada

4 Dept. of Pathology, Toronto General Hospital, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

5 Dept. of Biostatistics, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

6 Dalla Lana School of Public Health Sciences, University of Toronto, Toronto, ON, Canada

7 Dept. of Otolaryngology, Hospital Calderon Guardia, San Jose, Costa Rica

8 Dept. of Otolaryngology/Head and Neck Surgery, Worcester Royal Hospital, Worcester, UK

9 Dept. of Otolaryngology/Head and Neck Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland

10 Dept. of Otolaryngology/Surgical Oncology, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

11 Dept. of Computer Science, University of Toronto, Toronto, ON, Canada

12 Dept. of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada

13 Dept. of Medical Biophysics, University of Toronto, Toronto, ON, Canada

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BMC Cancer 2011, 11:437  doi:10.1186/1471-2407-11-437

Published: 11 October 2011

Abstract

Background

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. 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.

Methods

We 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.

Results

We 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).

Conclusion

Gene 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.

Keywords:
oral squamous cell carcinoma; surgical resection margins; global gene expression profiling; prognostic signature; recurrence