Chromosomal aberrations in premalignant and malignant squamous epithelium.

Biopsies of oropharyngeal cancer were screened for chromosomal imbalances by comparative genomic hybridization (CGH) performed on 22 primary tumors and morphologically nonmalignant surrounding mucosa. The aim was to determine early chromosomal changes of tumor development and to draw conclusions on the mechanisms leading to multiple tumors. The most prominent chromosomal imbalances observed were over representations of genomic material on 3q, 15q, 8q, and 11q and losses on 9p, 3p, and 11q. In morphologically normal mucosa collected at 1 cm from the primary tumor border (M1), amplifications on 15q and 21q were most frequent. Far fewer gains and losses were found in M1 than in the primary tumor (average 2.2 vs. 6.9). Gains dominated over losses, but a tendency toward an increasing proportion of losses in the primary tumor (PT) was observed (ratio of gains to losses: PT, 4.75; M1, 6.3). Almost all the imbalances in M1 were detected in the primary tumor. No chromosomal alterations were identified with CGH in tissue samples dissected at 2 cm from the primary tumor (M2). In all samples, dysplastic morphologic changes decreased with distance from the primary tumor, which correlates with the observed lower level of genetic changes. We suggest that gains of genetic material on 15q and 21q are early events in malignant progression of squamous cell carcinoma, followed by gains on 3q, 8q, and 11q, and losses on 3p and 9p at later stages. Based on our cytogenetic data, we discuss the monoclonal model followed by lateral epithelial spread as an explanation of multiple head and neck squamous cell carcinomas.

Patterns of chromosomal aberrations in metastasizing and nonmetastasizing squamous cell carcinomas of the oropharynx and hypopharynx.

Although several cytogenetic events of the tumor progression cascade have been identified in the past, the specific types of chromosomal alterations that lead to the development of lymph node metastases are still unknown. Operative specimens of 20 patients (10 patients with metastasizing tumors, 10 patients with nonmetastasizing tumors) with squamous cell carcinomas of the oropharynx and hypopharynx, along with the corresponding lymph node metastases, were investigated by quantitative DNA measurements and comparative genomic hybridization (CGH). Nonmetastasizing tumors (N0) displayed overrepresentations on chromosomes 10q (8 cases); 5p (7 cases); 3q and 20q (6 cases each); 8q (5 cases); 1p and 21q (4 cases each); 7p and 20p (3 cases each); and 2p, 15q, and 19q (2 cases each). Loss of chromosomal material was found on 5q, 9p, and 14q (2 cases each). Metastasizing tumors (N+) demonstrated overrepresentations on chromosomes 5p, 15q, and 22q (6 cases each); 3q and 11q13 (5 cases each); 20p and 21q (4 cases each); and 10q (3 cases). In 2 cases, an overrepresentation of the chromosomal arm 3q was accompanied by a loss of chromosomal arm 3p. Less frequent overrepresentations were observed on chromosomes 1q and 17q. Deletions were found on chromosomes 18q (3 cases), 3p, 4q, 5q, and 19p (2 cases each); and sporadic deletions occurred on 2q, 6q, 8p, 9p, 10p, 13q, 14q, 15q, and 16q. Whereas overrepresentations on chromosomes 1p and 7p occurred exclusively in N0 tumors, overrepresentations on chromosomes 1q, 11q, and 22q, along with deletions on 18q, were only observed in N+ tumors. Quantitative DNA measurements revealed a significantly higher percentage of aneuploid cells and a higher degree of DNA entropy in the N+ tumors. Chromosomal overrepresentations on chromosomes 1q, 8q, 11q, 18q, and 19q occurred more frequently in the metastases than in the corresponding primary tumors. Pairwise analysis of chromosomal alterations in the primary tumors and associated lymph node metastases revealed a genetic relationship, although a greater number of chromosomes on average were affected in the lymph node metastases. Quantitative DNA measurements demonstrated greater aneuploid values in the metastases. Recurring patterns of chromosomal alterations in N0 and N+ tumors were demonstrated in this study. In general, metastasizing tumors are characterized by overrepresentations on chromosomes 11q13 and 22q, and deletions on 18q. These aberrations suggest an elevation along the tumor progression cascade.