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A model of DNA aneuploidization and evolution in colorectal cancer
1Laboratory of Biophysics, National Institute for Cancer Research, Genoa, Italy.
Background:
Extensive chromosome and DNA content heterogeneity within and between human solid tumors has been observed using both classical karyotype and DNA cytometry. Experimental evidence suggests, at least in some tumor types, that DNA stemline heterogeneity in tumor progression is according to a three-compartment model with diploidy shifting to tetraploidy and then to hypotetraploidy.
Experimental Design:
The human colorectal adenoma-carcinoma sequence appears as one of the most potentially informative systems for the study of DNA stemline heterogeneity in human tumors since adenomas, adenomas with early cancer, and adenocarcinomas in nontreated patients represent clear morphologically distinct stages of tumor progression. The quantitative measurement of DNA content in the G0.1 phase of the cell cycle was performed by high resolution flow cytometry in a large number of cases using multiple fresh or frozen samples.
Results:
The distribution of the degree of DNA aneuploidy values, also known as DNA index, (DI not equal to 1) among 467 human precancer and cancer colorectal lesions was clearly nonrandom and showed modes at DI = 0.9, 1.2, 1.5, 1.8, and 2.2 with a clear valley at DI = 1.3. Whereas DNA aneuploid subclones within early lesions were up to about 80% near-diploid (DI < or = 1.3), DNA subclones within advanced cancer were in the vast majority with DI = 1.5-1.8 and, in a small fraction, with DI > 2. In addition, in adenomas with early cancer, which represent a link in colorectal tumor progression, early and late DNA stemlines often coexisted.
Conclusions:
The natural history of the colorectal adenoma-carcinoma sequence appears to be characterized by near-diploid subclones as early events and by late-stage hypotetraploidy. A new model is proposed that predicts the origin of the near-diploid subclones by "loss of symmetry" in cell division and their evolution (in particular hypodiploid) to the late-stage hypotetraploidy by tetraploidization. This model agrees with recent data associating molecular biology events, cytogenetic data, and DNA stemline heterogeneity in colorectal and other tumor systems.