Chromosomal imbalance in the progression of high-risk non-muscle invasive bladder cancer: a case control study

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 5 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 consecutive patients with “high-risk” non-muscle invasive bladder neoplasms, 67 with later disease progression, and 58 with no progression. 10 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 10K and 50K SNP microarrays to evaluate genome wide loss-of-heterozygosity and DNA copy number changes (fraction of genome 15 altered, progression-specific chromosomal alterations) 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 50K SNP microarrays). Results: Chromosomal instability did not predict any higher risk of subsequent progression. 20 Primary and recurrent stage T1/ high-grade tumors had generally more unstable genomes than recurrences of lower stage or grade. However, about 25% of the “high-risk” tumors had very few alterations, independent of the subsequent course. The CI of recurrent lesions, representing underlying field disease, did neither reflect a higher risk of progression. Of specific chromosomal alterations, a possible association between loss of chromosome 8p11 25