Tumor progression by dna flow cytometry in human colorectal cancer

Abstract

We wished to better understand the role of aneuploidy during the progression of human colorectal cancer. Fresh or frozen multiple samples from 221 human colorectal adenomas, 93 carcinomas, and corresponding control mucosa were investigated using high-resolution DNA flow cytometry. A total number of 164 DNA abnormal clones were observed and characterized by a quantitative index of DNA aneuploidy (DI). In precancerous lesions the vast majority of DNA abnormal clones (almost 3/4 in adenomas with mild to moderate dysplasia) was hypo- and hyper-diploid with DI values from 0.8 to 1.2 (near-diploidy). In moderately to poorly differentiated carcinomas the vast majority of abnormal clones was near-triploid and hypotetraploid with DI values from 1.4 to 1.8 (near hypertriploidy) and only 12% were near-diploid. Adenomas with foci of carcinomas, a group of special interest since they represent a link in colorectal tumor progression, had median triploid DNA content. In addition to an increase in DI values, the carcinomas had a clear increase in the proportion of cells actively synthesizing DNA (S-phase fraction). These results are interpreted as evidence for a ploidy-evolution model according to which near-diploid clones in adenomas at early stages of dysplasia would derive from abnormal mitotic cells that divide their DNA unequally between two daughter cells. Tetrapolidization of these near-diploid cells and successive DNA loss would then lead in later stages of tumor progression to near-hypertriploid clones characterized by a balance of chromosomes bearing growth-promoting and growth-suppressing genes confering a selective proliferative advantage.