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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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Copy number analysis of 15 marker regions (see Table 2). A: Kaplan Meier estimates of progression free survival according to number of copy-number imbalanced marker regions in QPCR analysis. Stable (0–2 changes); intermediate (3–4 changes), unstable (> 4 changes). B: Copy number alterations (log2 ratios) of candidate regions determined by SNP microarrays (SNPs flanking the marker regions). Tumors in columns, marker regions in rows. Top row indicates patient and tumor ID, bars below refer to tumor characteristics. Non-progressors to the left, progressors to the right; stage T1 tumors in the middle, stage Ta tumors on the flanks. Tumors are further sorted according to their CIS status: Tumors with concomitant CIS in the very center and on the very verges, tumors with later or no CIS in between. Furthermore, the grade of dysplasia (Bergkvist[15]), the actual clinical risk (including previous history)[3] and the used microarray (1 = 50 K, 2 = 10 K) are indicated. Data area: Red: Copy number gain. Blue: Copy number loss. C: Copy number analysis of the same candidate regions by QPCR of 101 tumors, hereof 77 independent tumors. Tumors are sorted in the same way as in B. A survey of the number of altered regions is provided in Additional File 7.
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Figure 3: Copy number analysis of 15 marker regions (see Table 2). A: Kaplan Meier estimates of progression free survival according to number of copy-number imbalanced marker regions in QPCR analysis. Stable (0–2 changes); intermediate (3–4 changes), unstable (> 4 changes). B: Copy number alterations (log2 ratios) of candidate regions determined by SNP microarrays (SNPs flanking the marker regions). Tumors in columns, marker regions in rows. Top row indicates patient and tumor ID, bars below refer to tumor characteristics. Non-progressors to the left, progressors to the right; stage T1 tumors in the middle, stage Ta tumors on the flanks. Tumors are further sorted according to their CIS status: Tumors with concomitant CIS in the very center and on the very verges, tumors with later or no CIS in between. Furthermore, the grade of dysplasia (Bergkvist[15]), the actual clinical risk (including previous history)[3] and the used microarray (1 = 50 K, 2 = 10 K) are indicated. Data area: Red: Copy number gain. Blue: Copy number loss. C: Copy number analysis of the same candidate regions by QPCR of 101 tumors, hereof 77 independent tumors. Tumors are sorted in the same way as in B. A survey of the number of altered regions is provided in Additional File 7.

Mentions: SNP microarray analysis (significance p = probability of detecting difference between progressing and non-progressing tumors by chance, permutation analysis). A survey of the entire genome is possible in Additional Files 2, 3, 4 and 5.


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)

Copy number analysis of 15 marker regions (see Table 2). A: Kaplan Meier estimates of progression free survival according to number of copy-number imbalanced marker regions in QPCR analysis. Stable (0–2 changes); intermediate (3–4 changes), unstable (> 4 changes). B: Copy number alterations (log2 ratios) of candidate regions determined by SNP microarrays (SNPs flanking the marker regions). Tumors in columns, marker regions in rows. Top row indicates patient and tumor ID, bars below refer to tumor characteristics. Non-progressors to the left, progressors to the right; stage T1 tumors in the middle, stage Ta tumors on the flanks. Tumors are further sorted according to their CIS status: Tumors with concomitant CIS in the very center and on the very verges, tumors with later or no CIS in between. Furthermore, the grade of dysplasia (Bergkvist[15]), the actual clinical risk (including previous history)[3] and the used microarray (1 = 50 K, 2 = 10 K) are indicated. Data area: Red: Copy number gain. Blue: Copy number loss. C: Copy number analysis of the same candidate regions by QPCR of 101 tumors, hereof 77 independent tumors. Tumors are sorted in the same way as in B. A survey of the number of altered regions is provided in Additional File 7.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2696467&req=5

Figure 3: Copy number analysis of 15 marker regions (see Table 2). A: Kaplan Meier estimates of progression free survival according to number of copy-number imbalanced marker regions in QPCR analysis. Stable (0–2 changes); intermediate (3–4 changes), unstable (> 4 changes). B: Copy number alterations (log2 ratios) of candidate regions determined by SNP microarrays (SNPs flanking the marker regions). Tumors in columns, marker regions in rows. Top row indicates patient and tumor ID, bars below refer to tumor characteristics. Non-progressors to the left, progressors to the right; stage T1 tumors in the middle, stage Ta tumors on the flanks. Tumors are further sorted according to their CIS status: Tumors with concomitant CIS in the very center and on the very verges, tumors with later or no CIS in between. Furthermore, the grade of dysplasia (Bergkvist[15]), the actual clinical risk (including previous history)[3] and the used microarray (1 = 50 K, 2 = 10 K) are indicated. Data area: Red: Copy number gain. Blue: Copy number loss. C: Copy number analysis of the same candidate regions by QPCR of 101 tumors, hereof 77 independent tumors. Tumors are sorted in the same way as in B. A survey of the number of altered regions is provided in Additional File 7.
Mentions: SNP microarray analysis (significance p = probability of detecting difference between progressing and non-progressing tumors by chance, permutation analysis). A survey of the entire genome is possible in Additional Files 2, 3, 4 and 5.

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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Related in: MedlinePlus