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Expression profiling by DNA microarray technology has identified genes associated with human tumor progression and provided molecular mechanisms underlying cancer development. Although differentially expressed genes along tumor progression have been related to genetic alterations occurring on chromosomes, it is not clear whether gene expression changes or chromosomal alterations occur randomly throughout the chromosomes or in distinct geographical “hot spots” during tumor progression and metastasis. Here we applied a novel bioinformatics approach, a technique testing homogeneous Poisson processes in chromosomal walking, on gene expression profiling from a progressive bladder cancer lung metastasis model. We found that overall, chromosome 2, 11 and 20 have higher than average proportion of significantly altered genes as a function of metastasis. In addition, chromosome 17q has a particularly active area of change or “hot spot” as a function of lung metastasis. Karyotyping of the cells reveals deletions on chromosome 11 and gains of chromosome 20 in progressively more metastatic competent cell lines, no correlation was found in chromosome 2 and 17 between gene expression result and karyotyping data. This suggests that gene expression as a function of metastatic progression are non random and may not always be associated with chromosomal changes. Furthermore, we sought to determine if these specific gene expression changes along chromosomes were relevant in human cancer by evaluating primary human bladder tumor samples. Since metastatic tissue from bladder cancer patient is not readily available and clinical stage is a strong predictor of metastasis we used stage comparisons as a surrogate for this latter phenotype. Here we detected chromosome 4, 17, 20, and Y as having the largest number of differentially expressed genes, and chromosome 17q, 8, 19, and Y harboring “hot spot” along human bladder cancer progression. In both lung metastatic model and human primary bladder tumor samples, chromosome 20 has higher than average proportion of significant genes and chromosome 17q has a “hot spot” suggesting that gene expression changes associated with metastasis are not random and that our lung metastatic model is relevant to human cancer. In summary, we find that gene expression changes during bladder cancer progression do not occur randomly, but instead occur both on specific chromosomes and intra-chromosomal locations. Furthermore, these changes are not always associated with karyotypic changes suggesting novel regional mechanisms controlling gene expression.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]