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Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer.

Zieger K, Wiuf C, Jensen KM, Ørntoft TF, Dyrskjøt L - BMC Cancer (2009)

Bottom Line: However, the predictive value was limited by the heterogeneity of the changes.Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression.About 25% of the "high risk" tumors were chromosomal stable.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Medicine, Aarhus University Hospital Skejby, Aarhus N, Denmark. karsten.zieger@ki.au.dk

ABSTRACT

Background: Non-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at "high risk" of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression.

Methods: To investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.We used Affymetrix GeneChip Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays).

Results: Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high-risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes.

Conclusion: Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression process. About 25% of the "high risk" tumors were chromosomal stable.

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Kaplan Meier estimates of progression-free survival according to chromosomal instability (CI). Tumors are divided in stable and unstable using a cut-off for the fraction of the genome altered (FGA) > 0.05. Here, the influence of the time to progression, not the relative size of the FGA is analysed. Logrank-tests for differences between progressing and non-progressing tumors showed no significant difference. A: all tumors, CI based on copy number changes (n = 46). B: all tumors, CI based on LOH (n = 47). C: Stage T1 tumors only, CI based on copy number changes (n = 32). D: Stage T1 tumors only, CI based on LOH (n = 33).
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Figure 1: Kaplan Meier estimates of progression-free survival according to chromosomal instability (CI). Tumors are divided in stable and unstable using a cut-off for the fraction of the genome altered (FGA) > 0.05. Here, the influence of the time to progression, not the relative size of the FGA is analysed. Logrank-tests for differences between progressing and non-progressing tumors showed no significant difference. A: all tumors, CI based on copy number changes (n = 46). B: all tumors, CI based on LOH (n = 47). C: Stage T1 tumors only, CI based on copy number changes (n = 32). D: Stage T1 tumors only, CI based on LOH (n = 33).

Mentions: The dataset was composed of 22 primary tumors (hereof 21 stage T1), and 26 recurrent tumors (hereof 15 stage T1). 27 patients had progressing disease, while 21 had no progression (see Additional File 1 for details). The probability of later progression was not associated with the fraction of the genome altered (FGA). Figure 1 illustrates the progression-free survival, dependent on whether the examined tumor was stable or unstable. Results of all tumors (corrected for stage) and separately for stage T1 tumors are shown. Figure 2 shows the relative significance of the FGA and its variation, dependent on whether later progression occurred or not. The FGA [CN] and FGA [LOH] for all individual tumors is listed in Additional File 7.


Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer.

Zieger K, Wiuf C, Jensen KM, Ørntoft TF, Dyrskjøt L - BMC Cancer (2009)

Kaplan Meier estimates of progression-free survival according to chromosomal instability (CI). Tumors are divided in stable and unstable using a cut-off for the fraction of the genome altered (FGA) > 0.05. Here, the influence of the time to progression, not the relative size of the FGA is analysed. Logrank-tests for differences between progressing and non-progressing tumors showed no significant difference. A: all tumors, CI based on copy number changes (n = 46). B: all tumors, CI based on LOH (n = 47). C: Stage T1 tumors only, CI based on copy number changes (n = 32). D: Stage T1 tumors only, CI based on LOH (n = 33).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2696467&req=5

Figure 1: Kaplan Meier estimates of progression-free survival according to chromosomal instability (CI). Tumors are divided in stable and unstable using a cut-off for the fraction of the genome altered (FGA) > 0.05. Here, the influence of the time to progression, not the relative size of the FGA is analysed. Logrank-tests for differences between progressing and non-progressing tumors showed no significant difference. A: all tumors, CI based on copy number changes (n = 46). B: all tumors, CI based on LOH (n = 47). C: Stage T1 tumors only, CI based on copy number changes (n = 32). D: Stage T1 tumors only, CI based on LOH (n = 33).
Mentions: The dataset was composed of 22 primary tumors (hereof 21 stage T1), and 26 recurrent tumors (hereof 15 stage T1). 27 patients had progressing disease, while 21 had no progression (see Additional File 1 for details). The probability of later progression was not associated with the fraction of the genome altered (FGA). Figure 1 illustrates the progression-free survival, dependent on whether the examined tumor was stable or unstable. Results of all tumors (corrected for stage) and separately for stage T1 tumors are shown. Figure 2 shows the relative significance of the FGA and its variation, dependent on whether later progression occurred or not. The FGA [CN] and FGA [LOH] for all individual tumors is listed in Additional File 7.

Bottom Line: However, the predictive value was limited by the heterogeneity of the changes.Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression.About 25% of the "high risk" tumors were chromosomal stable.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Medicine, Aarhus University Hospital Skejby, Aarhus N, Denmark. karsten.zieger@ki.au.dk

ABSTRACT

Background: Non-muscle invasive bladder neoplasms with invasion of the lamina propria (stage T1) or high grade of dysplasia are at "high risk" of progression to life-threatening cancer. However, the individual course is difficult to predict. Chromosomal instability (CI) is associated with high tumor stage and grade, and possibly with the risk of progression.

Methods: To investigate the relationship between CI and subsequent disease progression, we performed a case-control-study of 125 patients with "high-risk" non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. Selection criteria were conservative (non-radical) resections and full prospective clinical follow-up (> 5 years). We investigated primary lesions in 59, and recurrent lesions in 66 cases.We used Affymetrix GeneChip Mapping 10 K and 50 K SNP microarrays to evaluate genome wide chromosomal imbalance (loss-of-heterozygosity and DNA copy number changes) in 48 representative tumors. DNA copy number changes of 15 key instability regions were further investigated using QPCR in 101 tumors (including 25 tumors also analysed on 50 K SNP microarrays).

Results: Chromosomal instability did not predict any higher risk of subsequent progression. Stage T1 and high-grade tumors had generally more unstable genomes than tumors of lower stage and grade (mostly non-primary tumors following a "high-risk" tumor). However, about 25% of the "high-risk" tumors had very few alterations. This was independent of subsequent progression. Recurrent lesions represent underlying field disease. A separate analysis of these lesions did neither reflect any difference in the risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 and the risk of progression was found. However, the predictive value was limited by the heterogeneity of the changes.

Conclusion: Chromosomal instability (CI) was associated with "high risk" tumors (stage T1 or high-grade), but did not predict subsequent progression. Recurrences after "high-risk" tumors had fewer chromosomal alterations, but there was no association with the risk of progression in this group either. Thus, the prediction of progression of "high risk" non-muscle invasive bladder tumors using chromosomal changes is difficult. Loss of chromosome 8p11 may play a role in the progression process. About 25% of the "high risk" tumors were chromosomal stable.

Show MeSH
Related in: MedlinePlus