Elsevier

Oral Oncology

Volume 38, Issue 3, April 2002, Pages 266-273
Oral Oncology

Chromosomal changes in betel-associated oral squamous cell carcinomas and their relationship to clinical parameters

https://doi.org/10.1016/S1368-8375(01)00054-9Get rights and content

Abstract

To investigate the chromosomal imbalances that occur in oral carcinoma associated primarily with betel use and their clinical implications, we performed chromosomal analysis using comparative genomic hybridization on 47 patients with this disease. The most common gains of chromosome arms were 8q, 9q and 11q, and the most frequent losses were of chromosomal arms 3p and 4q. The clinical parameters significantly associated with the numbers of chromosomal imbalances per tumor were the age of the patients and nodal metastasis. The preliminary findings of a lower incidence of loss of 4q and gain of 8q in betel-associated tumors compared to non-betel-associated tumors might provide insight into the carcinogenic effect of betel. Deletion of 3p and the gain of 11q alterations were more prevalent in carcinomas with lymph node metastasis than in node-negative tumors, indicating possible loci for metastasis suppressor or metastasis enhancing genes, respectively. Losses of 3p and 4q and gain of 9q were associated with poor outcome for the patients. These data demonstrated that the frequent aberrations in 4q and 9q sites can be used as novel prognostic predictors.

Introduction

Carcinoma of the head and neck, including oral squamous cell carcinoma (OSCC), is the sixth most prevalent cancer worldwide [1], [2]. The majority of OSCC in industrialized societies are associated with tobacco or alcohol use. Betel use is a specific geographically-linked oral habit that is popular in South and Southeast Asia. Approximately 600 million people in this region are betel/tobacco users [3]. OSCC associated with the betel/tobacco use has become a very prevalent disease in this betel-using region, accounting for up to 50% of malignancy in some South Asia countries.[4] Due to the rapid expansion of betel-chewing population, this disease has become the fifth most common malignancy among the male population in Taiwan [5].

Considerable progress has been made in elucidating the genetic events underlying the development of OSCC. Genetic instability is an intrinsic feature of malignancies which is reflected by chromosomal alterations. Identification of aberrant chromosomal sites permits the construction of physical maps that target candidate genes. In recent years, comparative genomic hybridization (CGH) analysis has proved to be an important technique for identifying cytogenetic alterations [6], [7], [8]. This technique is more sensitive than the conventional karyotypic methods and provides more reliable data on comprehensive cytogenetic imbalances [8], [9]. Extensive CGH analysis of OSCC and head and neck squamous cell carcinoma (HNSCC) has resulted in a substantial understanding of many of the common cytogenetic abnormalities in these lesions [9], [10], [11], [12], [13], [14], [15]. Although the results of CGH analysis were not always consistent when different studies were compared, gains of chromosomal arms 8q, 3q, 20q, 11q and 9q as well as the losses of 4q, 3p, 5q, 15q and 18q were the prevailing genetic alterations identified in OSCC [9], [10], [11], [12], [13], [14], [15]. The results were based on lesions caused primarily by the combined effects of tobacco and alcohol associated with OSCC in industrialized societies. No data concerning the chromosomal alterations in OSCC related to betel use was previously available. Thus, a study of chromosomal damages in betel-associated OSCC will have important and obvious implications in resolving the pathogenesis associated with betel exposure.

Determining the genetic events that are involved in metastasis and identifying molecular markers with prognostic significance may offer an opportunity to develop therapies for OSCC based on individual tumor characteristics. Previously, allelic analysis has been used to enhance our knowledge of molecular events in carcinogenesis. For instance, loss of 3p and 9p were identified as the most significant pathogenetic events of HNSCC [16], [17], [18], [19]. They have been widely used to predict the outcome of oral cancer and the malignant potential of precancerous lesions [18], [19]. However, allelic analysis is only feasible when a precise assessment of certain allelic fragments is possible. The primarily unbalanced chromosomes found in betel-associated OSCC and their clinical implications have yet to be unraveled. CGH allows a comprehensive survey of all cytogenetic alterations in a cancer and we apply this technique in this study to evaluate the clinical and prognostic significance of karyotypic aberrations in betel-associated OSCC.

Section snippets

Subjects

Forty-seven OSCC obtained from the surgically resected samples in the Veterans General Hospital-Taipei between 1997 and 1998 were investigated. Approximately three-quarters (35/47) of the tumors were at an advanced stage, as measured by the guidelines of the American Joint Committee on Cancer. All betel users had histories of betel consumption of more than 10 pack-years. All tobacco users had smoked tobacco at a rate of more than 10 pack-years. All betel users were also tobacco smokers. The

Genetic changes

Thirty-one of the 47 (66%) OSCCs showed cytogenetic alterations by CGH. Cumulative results for each chromosome are illustrated in Fig. 1. There were 5.8±1.1 total alterations/tumor, consisting of 3.6±0.7 gains and 2.1±0.5 losses (Table 1). Gains were most frequently observed on chromosomes 8q (32%), 9q (26%), 11q (23%), 17q (21%) and 20q (19%). The minimal overlapping regions were at 8q24, 9q34, 11q13, 17q21, 17q25 and 7p22 (Fig. 1). Losses frequently involved chromosomes 3p (34%), 4q (23%), 5q

Discussion

The results of this CGH study provide insights into the cytogenetic changes that occur in OSCC. The profile of chromosomal alterations, with gains in 8q, 9q, 11q, 17q and 20q and losses in 3p, 4q, 5q, 9p and 18q, was largely compatible with previous studies [9], [10], [11], [12], [13], [14], [15]. Nevertheless, the incidence of chromosomal alterations revealed by our study is relatively lower than that reported in previous studies. This discrepancy may be due to the relatively high frequency of

Acknowledgments

We gratefully acknowledge Dr. Kathy A. Mangold for her critical review on this manuscript. This work was supported by grant NHRI-GT-EX89S927P from the National Health Research Institute (to Lin, S-C), 89-B-FA22-2-4 from the Program for Promoting Academic Excellence of Universities (to Hsu, M-T) and the Medical Research and Advancement Foundation in Memory of Dr. Chi-Shuen Tsou.

References (27)

  • A. Kallioniemi et al.

    Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors

    Science

    (1992)
  • P.H. Rooney et al.

    Comparative genomic hybridization and chromosomal instability in solid tumours

    British Journal of Cancer

    (1999)
  • M. Okafuji et al.

    Identification of genetic aberrations in cell lines from oral squamous cell carcinomas by comparative genomic hybridization

    Journal of Oral Pathology and Medicine

    (1999)
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