Congenital genetic instability in colorectal carcinomas.

INTRODUCTION

Oncogenic evolution is probably based on a progressive selection of clonal subpopulations from within a single clone. This selection is supposed to be based on enhanced genetic instability in the genome. In the vast majority of patients this increased lability is supposed to be the result of acquired alterations, and once established, it may contribute to the continuing, genetic instability within the neoplastic cells. It has been postulated, that inborn chromosomal instability is not limited to a few rare syndromes. Indeed, one of the common colorectal cancer (CRC) syndromes, familial adenomatous polyposis (FAP), is supposed to be a chromosomal instability syndrome. Also the hereditary nonpolyposis colorectal cancer syndrome (Lynch Syndrome (LS)) has shown genomic instability. Knudson (1971, 1985) has shown, that the same gene can be involved in both the hereditary form of a cancer and in the sporadic form of the same cancer. Due to the existence of such hereditary chromosomal instability syndromes, inherited genetic instability may be of some importance in the evolution of sporadic colorectal cancers.

METHODS

In vitro research on dermal fibroblasts is based on the theory, that all studied cells of an individual carry the same genetic material, irrespective of their in vivo expression. Increased in vitro tetraploidy (IVT+) in skin fibroblast cultures is supposed to be a germinally transmitted expression of genomic instability, with special reference to LS. At the same time the chromosomal aberrations, which occur in neoplasms, can be measured by flow cytometric DNA analysis. The DNA content, thus measured, is supposed to be an expression of somatic acquired genetic instability. Finally, since occult mandibular osteomas have been shown to be associated with FAP, we have investigated a substantial part of our patients with this phenotypical marker.

AIM OF STUDY

In CRC the adenoma-carcinoma sequence is widely accepted, and the purpose of our investigation was to find a correlation, if any, between: Changes in adenoma flow cytometric DNA content and histological grade and type of adenomas. Changes in dermal fibroblast IVT+ from adenoma patients and histological grade and type of adenomas. Changes in dermal fibroblast IVT+ and flow cytometrical DNA content in adenomas and carcinomas from the same patients. Furthermore, we wanted to investigate if: The occurrence of IVT+ in skin fibroblasts among patients with CRC was different from that of IVT+ among patients without colorectal neoplasies. The occurrence of IVT+ in skin fibroblasts among patients with CRC was associated with the occurrence of occult mandibular osteomas in the same patients. The occurrence of dermal fibroblast IVT+ conveyed any prognostic significance in CRC patients.

RESULTS AND CONCLUSIONS

1. A significant correlation was found between both the occurrence of skin fibroblast IVT+ and adenoma DNA aneuploidy in relation to the degree of dysplasia and histological type of adenomas. This signifies, that inborn and acquired genetic instability is correlated to the adenoma-carcinoma sequence. IVT+ was found to be correlated to the progression of adenomas to carcinomas and not to the development of adenomas. 2) A direct correlation between IVT+ and adenoma DNA aneuploidy could not be demonstrated. However, among those patients with diploid adenomas and IVT+ 57% showed villous adenomas. Among those patients with diploid adenomas and IVT- only 14% had villous adenomas. This further substantiates the correlation of IVT+ to the adenoma-carcinoma sequence. IVT+ was highly associated with DNA aneuploidy in carcinomas, and since IVT+ was found to be significantly associated with CRC's with a DNA index > or = 1.5, it is suggested that IVT+ mainly is correlated to the early steps in tumor progression. 3) IVT+ was found in 34% of sporadic CRC, and tumor DNA aneuploidy was demonstrated in 73%...