The Combination of SMAD4 Expression and Histological Grade of Dysplasia Is a Better Predictor for the Malignant Transformation of Oral Leukoplakia

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Abstract

Oral leukoplakia (OL) is the most common premalignancy in the oral cavity and can progress to oral squamous cell carcinoma (OSCC). SMAD4 is a tumor suppressor implicated in multiple cancer types including OSCC. To assess the role of SMAD4 in oral leukoplakia malignant transformation, the authors investigated SMAD4 expression patterns in OL and OSCC using a highly specific antibody and correlated the patterns with the risk of malignant transformation oral leukoplakia. Immunohistochemistry and a quantitative imaging system were used to measure SMAD4 expression in OL from 88 OL patients, including 22 who later went through malignant transformation, and their OSCC counterpart. Forty-three (48.9%) of the 88 OL patients had strong SMAD4 expression. SMAD4 expression had no significant correlation with patients' clinicopathological parameters. Interestingly, 17 (39.5%) of the 43 OL lesions with strong SMAD4 expression went through malignant transformation whereas only 5 (11.1%) of the 45 OL lesions with weak SMAD4 expression did so (p = 0.002). The SMAD4 expression in OL was much higher than that in their OSCC counterpart. Kaplan-Meier analysis revealed that the combination of SMAD4 expression and histological grade of dysplasia (p = 0.007) is a better predictor for the malignant transformation of oral leukoplakia. In the multivariate analysis, both SMAD4 expression and grade of dysplasia were identified as independent factors for OL malignant transformation risk (p = 0.013 and 0.021, respectively). It was concluded that high SMAD4 expression may be indicative of an early carcinogenic process in OL and serve as an independent biomarker in assessing malignant transformation risk in patients with OL, and the combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia.

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Most cited references 23

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Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

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Nomenclature and classification of potentially malignant disorders of the oral mucosa.

S Warnakulasuriya, Newell W. Johnson, I Van der Waal (2007)

At a workshop coordinated by the WHO Collaborating Centre for Oral Cancer and Precancer in the UK issues related to terminology, definitions and classification of oral precancer were discussed by an expert group. The consensus views of the Working Group are presented here. The term, 'potentially malignant disorders', was recommended to refer to precancer as it conveys that not all disorders described under this term may transform into cancer. Critically evaluating all definitions proposed so far for oral leukoplakia, the Working Group agreed that the term leukoplakia should be used to recognize 'white plaques of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer'. An outline was proposed for diagnosing oral leukoplakia that will prevent other oral white disorders being misclassified as leukoplakia. The Working Group discussed the caveats involved in the current use of terminology and classification of oral potentially malignant disorders, deficiencies of these complex systems, and how they have evolved over the past several decades. The terminology presented in this report reflects our best understanding of multi-step carcinogenesis in the oral mucosa, and aspires to engender consistency in use.

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Author and article information

Contributors

Mohammad O. Hoque: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 24 June 2013

Volume: 8

Issue: 6

Electronic Location Identifier: e66794

Affiliations

[1 ]Department of Oral Pathology, 9th People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China

[2 ]Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, United States of America

[3 ]Department of Oral Maxillofacial–Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China

[4 ]Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, United States of America

Johns Hopkins University, United States of America

Author notes

* E-mail: lijiang182000@ 123456yahoo.com (JL); LMao@ 123456umaryland.edu (LM)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: XJW LM JL. Performed the experiments: RHX XMS. Analyzed the data: RHX XMS XJW LM JL. Contributed reagents/materials/analysis tools: RHX XMS XJW. Wrote the paper: RHX LM JL.

Article

Publisher ID: PONE-D-13-01556

DOI: 10.1371/journal.pone.0066794

PMC ID: 3691281

PubMed ID: 23826135

SO-VID: 59a8d788-3147-448e-9457-c8d285f72382

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 4 January 2013

Date accepted : 13 May 2013

Page count

Pages: 6

Funding

This work was supported by Chinese Nature Science Foundation (81272976, 30872905 and 81072211), the Shanghai Leading Academic Discipline Project (S30206) and the Doctoral Innovation Foundation of Shanghai Jiao Tong University, School of Medicine (BXJ201029). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The Combination of SMAD4 Expression and Histological Grade of Dysplasia Is a Better Predictor for the Malignant Transformation of Oral Leukoplakia

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Most cited references 23

Cancer Statistics, 2008

Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

Nomenclature and classification of potentially malignant disorders of the oral mucosa.

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