Thomas Ried

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), and 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-1 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.

We present a technique which allows the detection and chromosomal localization of DNA sequence copy number changes in solid tumor genomes from frozen sections and paraffin embedded, formalin fixed specimens. Based on comparative genomic hybridization and on universal DNA amplification procedures this technique is possible even if only a few tumor cells are available. We demonstrate the feasibility of this method to visualize complete and partial chromosome gains and losses and gene amplifications in archived solid tumor samples.

Small-cell lung cancer (SCLC) represents a group of highly malignant tumors giving rise to early and widespread metastases. We used comparative genomic hybridization in autoptic tumor specimens from 10 patients to discover genetic alterations that are associated with tumor progression and potentially with the metastatic phenotype. Ten primary SCLC and 16 corresponding metastases were investigated with a maximum of 4 tumors per case. Prevalent changes observed in more than 60% of the primary tumors and their metastases included deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p, and DNA over-representations on chromosomes 3q and 5p. The number of common alterations in the primary tumors and the related metastases outnumbered the differences, indicating a clonal relationship. Within the lesions of the same patient, differences were found between the primary tumor and the metastases as well as between metastases of distinct organ sites. However, no specific alteration was significantly associated with the metastatic phenotype. We suggest that the high malignancy of SCLC is defined by the above-mentioned pattern of aberrations.