Redefining the Significance of Aneuploidy in the Prognostic Assessment of Colorectal Cancer

Abstract

SUMMARY:The aberrant content of DNA, or aneuploidy, is a hallmark of tumor cells and may be associated with malignant potential. Based on the hypothesis that aneuploidy, as a form of genetic instability, results in an increased capability to generate cell heterogeneity, we investigated whether a comprehensive assessment of aneuploidy extent and degree might be a reliable indicator of tumor aggressiveness. DNA content was determined by flow cytometry in the infiltrating front of 131 paraffinembedded primary colorectal carcinomas collected in a prospective design. Enrichment of tumor cells by sample microdissection resulted in neoplastic cell contents above 75%. An estimate of aneuploidy, the aneuploidy index (AI), was calculated as the tumor DNA content adjusted by the percentage of diploid and aneuploid cells in G0/G1. Thirty-nine tumors were diploid, 90 hyperdiploid, and 2 hypodiploid. The mean AI in aneuploid tumors was 1.20 Ϯ 0.17 and correlated with Dukes' stage and metastasis (p Ͻ 0.05). A high AI (receiver operating characteristic curve cutoff value greater than 1.14) predicted a poorer outcome in univariate (p ϭ 0.004) and multivariate (p ϭ 0.01) analyses. Based on these results, we postulate that aneuploidy is the molecular engine of progression in a subset of colorectal cancers, in which the AI seems to be a sensible and independent gauge of malignant potential. The AI determination may have prognostic application in colorectal cancer, especially in low-grade tumors, which might benefit from coadjuvant therapies. (Lab Invest 2001, 81:307-315).

DNA Ploidy Status and Prognosis in Colorectal Cancer: A Meta-Analysis of Published Data

“…In these 25 studies, it was observed that the duration of followup was inaccurate or did not reach five years after surgical treatment. Nineteen studies 29,48,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78] were excluded because of impossible data extraction. In these studies, survival data tables or curves at fiveyear follow-up were not available or absolute death numbers were available but the group size was not determined at the beginning of follow-up or after five years.…”

Effects of hTERT on metal ion-induced genomic instability

“…It is interesting that an example of transformation to a near tetraploid state has been described in tissue culture of Barrett's epithelium, which was transfected with hTERT (Corinna et al, 2003). This transformation coupled with repeated exposure to DNA-damaging agents may drive a malignant process to complex aneuploidy with a consequent poor prognosis (Risques et al, 2003).…”

Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis

“…Generally, a more detailed assessment—for example, using array comparative genomic hybridisation (arrayCGH)—is impractical for large series. Nonetheless, many studies have reported that CIN+ measured by flow cytometry confers a worse prognosis; however, this observation is neither universal5 6 nor always significant 7 – 9. Consequently, it has been argued consistently that measuring CIN does not add further prognostic information to standard pathological and histological staging 10 – 13.…”