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Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.

Lindgren D, Sjödahl G, Lauss M, Staaf J, Chebil G, Lövgren K, Gudjonsson S, Liedberg F, Patschan O, Månsson W, Fernö M, Höglund M - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathology, Lund University, Malmö, Sweden.

ABSTRACT
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.

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DNA copy number alterations in 146 bladder tumors.A) Whole genome heatmap representing relative copy number profiles of the samples. Segments of gains or deletions are color-coded according their relative log2 copy number ratios. B) DNA copy number frequency plot of gains (red) and losses (blue). Above: Recurrent high-level focal amplifications (FGA; red) are indicated by red bars and labeled according to their cytogenetic localization. Below: Recurrent homozygous deleted regions (HD; blue) and recurrent minimal regions of deletions (MRD; green) labeled according to their respective cytogenetic localization.
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pone-0038863-g001: DNA copy number alterations in 146 bladder tumors.A) Whole genome heatmap representing relative copy number profiles of the samples. Segments of gains or deletions are color-coded according their relative log2 copy number ratios. B) DNA copy number frequency plot of gains (red) and losses (blue). Above: Recurrent high-level focal amplifications (FGA; red) are indicated by red bars and labeled according to their cytogenetic localization. Below: Recurrent homozygous deleted regions (HD; blue) and recurrent minimal regions of deletions (MRD; green) labeled according to their respective cytogenetic localization.

Mentions: We performed genome wide DNA copy number profiling of 146 cases of UCs using tiling-resolution BAC arrays (Figure 1A). Genomic regions particularly affected by copy number gains were observed on chromosome arms 1q, 3p, 3q, 5p, 6p, 8q, 18p, 20p, and 20q, whereas deletions were common on 2q, 5q, 8p, 9p, 9q, 10q, 11p, 13q, 17p, and 22q (Figure 1B). In line with previous reports, a strong association between increasing numbers of copy number alterations and pathological stage and grade was observed (Figure 1A and Figure S2). Grade 1 tumors carried few alterations: primarily deletions of 9q, but also occasional deletions of 9p and gains of 1q whereas G2 tumors showed a slightly wider spectrum of aberrations. In particular, the frequency of CDKN2A deletions was increased in G2 compared to G1; 48% vs. 16% (Figure S2A). A major transition with respect to genomic alterations was observed between G2 and G3 tumors as G3 tumors harbored markedly higher numbers of genomic alterations (Figs. 1A and S2A).


Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.

Lindgren D, Sjödahl G, Lauss M, Staaf J, Chebil G, Lövgren K, Gudjonsson S, Liedberg F, Patschan O, Månsson W, Fernö M, Höglund M - PLoS ONE (2012)

DNA copy number alterations in 146 bladder tumors.A) Whole genome heatmap representing relative copy number profiles of the samples. Segments of gains or deletions are color-coded according their relative log2 copy number ratios. B) DNA copy number frequency plot of gains (red) and losses (blue). Above: Recurrent high-level focal amplifications (FGA; red) are indicated by red bars and labeled according to their cytogenetic localization. Below: Recurrent homozygous deleted regions (HD; blue) and recurrent minimal regions of deletions (MRD; green) labeled according to their respective cytogenetic localization.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369837&req=5

pone-0038863-g001: DNA copy number alterations in 146 bladder tumors.A) Whole genome heatmap representing relative copy number profiles of the samples. Segments of gains or deletions are color-coded according their relative log2 copy number ratios. B) DNA copy number frequency plot of gains (red) and losses (blue). Above: Recurrent high-level focal amplifications (FGA; red) are indicated by red bars and labeled according to their cytogenetic localization. Below: Recurrent homozygous deleted regions (HD; blue) and recurrent minimal regions of deletions (MRD; green) labeled according to their respective cytogenetic localization.
Mentions: We performed genome wide DNA copy number profiling of 146 cases of UCs using tiling-resolution BAC arrays (Figure 1A). Genomic regions particularly affected by copy number gains were observed on chromosome arms 1q, 3p, 3q, 5p, 6p, 8q, 18p, 20p, and 20q, whereas deletions were common on 2q, 5q, 8p, 9p, 9q, 10q, 11p, 13q, 17p, and 22q (Figure 1B). In line with previous reports, a strong association between increasing numbers of copy number alterations and pathological stage and grade was observed (Figure 1A and Figure S2). Grade 1 tumors carried few alterations: primarily deletions of 9q, but also occasional deletions of 9p and gains of 1q whereas G2 tumors showed a slightly wider spectrum of aberrations. In particular, the frequency of CDKN2A deletions was increased in G2 compared to G1; 48% vs. 16% (Figure S2A). A major transition with respect to genomic alterations was observed between G2 and G3 tumors as G3 tumors harbored markedly higher numbers of genomic alterations (Figs. 1A and S2A).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pathology, Lund University, Malmö, Sweden.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus