Abstract 3109: Correlation between genomic aberrations and the DNA damage response in bladder cancer
Authors: Schepeler Troels , Lamy Philippe , Laurberg Jens , Fristrup Niels , Bartkova Jirina , Hvidbjerg Vibeke , Tropia Laurence , Bartek Jiri , Halazonetis Thanos D. , Reinert Thomas , Borre Michael , Dyrskjøt Lars , Ørntoft Torben F. 
Published: August 2012

Abstract
Carcinogenesis is paralleled by ongoing insults to tumor genome integrity, commonly sensed and reacted to by the DNA damage response (DDR). The DDR is thought to act as an inducible barrier against early tumor development, but, if compromised, may allow tumor progression and rampant genomic instability. However, the interplay between the DDR, genomic integrity, and tumor development is still poorly understood. To extend current knowledge of these issues, we analyzed 45 human bladder tumors from 22 patients using a combination of Affymetrix Genome-Wide Human SNP Arrays 6.0 and immunohistochemistry (IHC). This allowed us to characterize genomic aberrations at high resolution, and determine the tissue expression patterns of several DDR components in the context of the underlying genomic complexity. The complexity of individual SNP-profiles varied considerably and widespread aberrations included novel features such as 151 copy neutral loss of heterozygosity (LOH) regions. Some of these were of potential functional relevance because they spanned mutated FGFR3 and PIK3CA alleles, in addition to a homozygous deletion involving the p16 tumor suppressor locus at chr9p22. In fact, most (34/60) homozygous deletions identified were confined to this region. The SNP-profiles also showed that metachronous tumors generally had several aberrations in common, thus suggesting a clonal relationship. We partitioned tumor-derived SNP-profiles into three groups of increasing complexity, likely to reflect histories of varying genomic instability, and compared these to IHC results. DDR tissue staining patterns using phospho-specific antibodies against p53, γH2AX, ATR, and ATM, indicative of an activated DDR, were not correlated to the total sum of accumulated DNA damage. Rather, the most complex tumor genomes were associated with absence of p16 expression, a high Ki67-proliferation index, and abundant expression of the multifunctional DDR protein Timeless. Tipin, an important interaction partner of Timeless, was expressed without any association to Timeless staining patterns and genomic integrity. Interestingly, in a large cohort of more than 250 non-muscle invasive bladder tumors, Timeless expression was associated with risk of progression to muscle-invasive disease (p&lt;0.001; HR, 2.4; 95% CI, 1.6-3.8). In conclusion, we generated a high-resolution analysis of bladder tumor genomes and identified novel regions of potential functional relevance, including several copy neutral LOH regions. Moreover, we showed that the overall complexity of tumor genomes is not closely associated to common phosphorylation events within the DDR but instead involves p16 loss, high Ki67 index, and abundant Timeless expression. Finally, evaluation of Timeless expression by IHC may improve current approaches to estimate risk of progression in non-muscle invasive bladder tumors based on established histopathological variables.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3109. doi:1538-7445.AM2012-3109