Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.
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 E2F3, CCND1, and CCNE1, as well as new candidate genes, such as SETDB1 (1q21), and BCL2L1 (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 FGFR3 alterations, overexpression of CCND1, and 9q and CDKN2A deletions. The second circuit was defined by E3F3 amplifications and RB1 deletions, as well as gains of 5p, deletions at PTEN and 2q36, 16q, 20q, and elevated CDKN2A levels. TP53/MDM2 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.
Department of Molecular Pathology, Lund University, Malmö, Sweden.
David
D
Lindgren
Gottfrid
G
Sjödahl
Martin
M
Lauss
Johan
J
Staaf
Gunilla
G
Chebil
Kristina
K
Lövgren
Sigurdur
S
Gudjonsson
Fredrik
F
Liedberg
Oliver
O
Patschan
Wiking
W
Månsson
Mårten
M
Fernö
Mattias
M
Höglund
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D046888:Tissue Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2