Integrated Genomic and Gene Expression Profiling Identifies Two Major Genomic Circuits in Urothelial Carcinoma

Abstract

<div><p>Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions. Several potential oncogenes were included in the amplified regions, including known oncogenes like <em>E2F3</em>, <em>CCND1</em>, and <em>CCNE1</em>, as well as new candidate genes, such as <em>SETDB1</em> (1q21), and <em>BCL2L1</em> (20q11). We next combined genome profiling with global gene expression, gene mutation, and protein expression data and identified two major genomic circuits operating in urothelial carcinoma. The first circuit was characterized by <em>FGFR3</em> alterations, overexpression of <em>CCND1</em>, and 9q and <em>CDKN2A</em> deletions. The second circuit was defined by <em>E3F3</em> amplifications and <em>RB1</em> deletions, as well as gains of 5p, deletions at <em>PTEN</em> and 2q36, 16q, 20q, and elevated <em>CDKN2A</em> levels. <em>TP53/MDM2</em> alterations were common for advanced tumors within the two circuits. Our data also suggest a possible RAS/RAF circuit. The tumors with worst prognosis showed a gene expression profile that indicated a keratinized phenotype. Taken together, our integrative approach revealed at least two separate networks of genomic alterations linked to the molecular diversity seen in UC, and that these circuits may reflect distinct pathways of tumor development.</p> </div