We have chosen tumors of the uterine cervix as a model system to identify chromosomal aberrations that occur during carcinogenesis. A phenotype/genotype correlation was established in defined regions of archived, formalinfixed, and hematoxylin/eosin-stained tissue sections that were dissected from normal cervical epithelium (n = 3), from mild (n = 4), moderate (n = 6), and severe dysplasias/carcinomas in situ (CIS) (n = 13), and from invasive carcinomas (n = 10) and investigated by comparative genomic hybridization. The same tissues were analyzed for DNA ploidy, proliferative activity, and the presence of human papillomavirus (HPV) of the carcinomas and was also found to have undergone a high-level copy-number increase (amplification). We therefore conclude that the gain of chromosome 3q that occurs in HPV16-infected, aneuploid cells represents a pivotal genetic aberration at the transition from severe dysplasia/CIS to invasive cervical carcinoma.The multistep nature of carcinogenesis is firmly established (1-4). The sequence of genetic aberrations can be studied best in organs in which a histomorphological phenotype is defined for certain stages of tumor progression-e.g., colon cancer (5) and cancer of the uterine cervix. Regarding carcinomas of the cervix, infection with human papillomavirus (HPV) is known to play a crucial role in the immortalization of epithelial cells (6, 7). However, the persistence of HPV infection in women that do not develop dysplasias or carcinomas (8) and the long latency of the transition from severe dysplasia/carcinoma in situ (CIS) to carcinoma strongly suggest that factors in addition to HPV infection are required for the malignant transformation of epithelial cells (9). In analogy to colon carcinogenesis, mutations affecting tumor-suppressor genes or cellular oncogenes are likely candidates for additional "hits." Cytogenetically, those mutations are often present as specific chromosomal aberrations. However, relatively little is known about tumor-specific recurrent chromosomal aberrations in dysplastic lesions and primary invasive carcinomas of the uterine cervix-the second most frequent carcinoma in women worldwide-despite the fact that the importance of chromosomal aberrations in cervical carcinogenesis was recognized some 25 years ago (10). However, to date no landmark aberrations have been identified in cervical carcinomas (11, 12).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.The scarcity of data on recurrent chromosomal aberrations that occur during the initiation and progression of cervical tumors prompted us to screen tissue from defined stages of cervical tumorigenesis by a molecular cytogenetic approach termed comparative genomic hybridization (CGH) (13,14). CGH serves as a screening test for DNA copy-number changes in tumor genomes. CGH is based on a two-color fluorescence in situ hybridization, whe...

Comparative genomic hybridization was used to screen the DNA extracted from histologically defined tissue sections from consecutive stages of colorectal carcinogenesis for chromosomal aberrations. No aberrations were detected in normal epithelium (n = 14). Gain of chromosome 7 occurred as a single event in low‐grade adenomas (n = 14). In high‐grade adenomas (n = 12), an overrepresentation of chromosomes 7 and 20 was present in 30% of the cases analyzed. The transition to colon carcinomas (n = 16) was characterized by the emergence of multiple chromosomal aberrations. Chromosomes 1, 13, and 20 and chromosome arms 7p and 8q were frequently gained, whereas chromosome 4 and chromosome arms 8p and 18q were recurrently underrepresented. The same tissue sections that were used for CGH were analyzed by means of DNA‐ploidy measurements and immunohistochemical staining to quantify proliferative activity and p21/WAF‐I and TP53 expression. We observed that crude aneuploidy and increased proliferative activity are early events in colorectal carcinogenesis, followed by TP53 overexpression and the acquisition of recurrent chromosomal gains and losses during the progression from high‐grade adenomas to invasive carcinomas. Genes Chromosom Cancer (1996). © 1996 Wiley‐Liss, Inc.

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