DNA Aneuploidy by Flow Cytometry Is an Independent Prognostic Factor in Gastric Cancer

Abstract

In the present study the prognostic value of both DNA ploidy and the proliferative activity of tomour cells were studied in a series of 76 consecutive patients suffering from gastric tumours. DNA ploidy and the proliferative index (as measured by the percentage of S-phase cells) were determined by flow cytometry using fresh tumour specimens.The presence of DNA aneuploid clones by flow cytometry was detected in 62% of the cases (mean DNA index of 1.63 ± 0.46; range 1.08–2.92), the mean proportion of S-phase cells being of 18.4 ± 11.5%. In comparison with diploid cases, aneuploid tumours showed a higher proliferative activity (cases with more than 15% S-phase cells: 18.4% versus 6.1%, p = 0.0001) as well as a higher incidence of node involvement (95% versus 68%, p = 0.001). By contrast, no significant differences were detected with respect to sex, age, histologic grade and type, clinical stage, tumour size and the incidence of extranodal involvement.Upon grouping the patients according to the proportion of S-phase cells no significant differences were observed for the clinical and biological parameters explored except for an association between a high percentage of S-phase cells and the presence of DNA aneuploidy (40% versus 96%, p = 0.0001). Regarding survival the presence of DNA aneuploidy was significantly associated with poor outcome as compared to the diploid cases (median of 15 versus 26 months, p = 0.005). By contrast, the proportion of S-phase cells did not predict patients’s outcome.Multivariate analysis of prognostic factors showed that the presence of DNA aneuploidy (p = 0.003) together with the histologic type (p = 0.03) and the existence of extranodal metastases (p = 0.05) were the best combination of prognostic factors for survival prediction.

Promoter hypermethylation of the Chfr gene in neoplastic and non-neoplastic gastric epithelia

“…Although CIN is one of the most frequently recognised phenomenon in gastric cancer (Abad et al, 1998;Esteban et al, 1999;Russo et al, 2000), the mitotic checkpoint genes hsMAD2 and hBUB1 are rarely mutated in gastric and other types of human malignancy (Imai et al, 1999;Tanaka et al, 2001). Checkpoints upstream of the spindle checkpoint that delays chromosome condensation in response to mitotic stress are regulated by CHFR.…”

“…This suggests that Chfr promoter hypermethylation may be an early event in gastric carcinogenesis. DNA aneuploidy has been observed in 50 -71% of gastric cancers and correlates with poor prognosis (Abad et al, 1998;Esteban et al, 1999;Russo et al, 2000). In the present study, we failed to find a statistically significant correlation between Chfr hypermethylation and gastric cancer patient survival.…”

“…A small fraction of CIN cancers are associated with dominant mutations in the human homologues of yeast spindle checkpoint genes BUB1 (Cahill et al, 1998;Imai et al, 1999;Gemma et al, 2000) and MAD2 (Li and Benezra, 1996;Cahill et al, 1999). However, BUB1 and MAD2 mutations are relatively rare, and gastric cancers frequently exhibit DNA aneuploidy (Abad et al, 1998;Esteban et al, 1999;Imai et al, 1999;Russo et al, 2000;Tanaka et al, 2001).…”

Contenido de ADN y sobrevida en el carcinoma subseroso de la vesícula biliar

“…Se asume que esta heterogeneidad es el reflejo de la heterogeneidad genética a nivel celular, por lo cual un mismo tumor puede presentar clones con un distinto patrón de ploidia. Ha sido demostrado que cantidades anormales de ADN en las células tumorales son un factor pronóstico en algunas neoplasias 12,15,16 . Existe escasa información respecto del cáncer de la vesícula biliar y contenido de ADN y, menos aún, en relación al grupo de carcinomas subserosos [17][18][19][20] .…”

“…El contenido aneuploide de ADN está relacionado con la existencia de poblaciones celulares cuyo comportamiento biológico puede variar considerablemente 11,12 . Se ha demostrado que la medición de la ploidia a través de citometría de flujo es una herramienta complementaria en la caracterización de diferentes procesos neoplásicos 13,14 .…”