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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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Associations between chromosomal aberrations visualized by MDS.Recurrent FGAs, HDs, and MRDs, as well as recurrent large chromosome arm deletions were included in the analysis. FGAs and HDs present in <5% of samples were excluded. Aberrations with significant positive associations, as determined by hypergeometric tests, are indicated in red and connected with green lines. Aberrations located to the same chromosomes are circled in gray for visualization purposes.
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pone-0038863-g002: Associations between chromosomal aberrations visualized by MDS.Recurrent FGAs, HDs, and MRDs, as well as recurrent large chromosome arm deletions were included in the analysis. FGAs and HDs present in <5% of samples were excluded. Aberrations with significant positive associations, as determined by hypergeometric tests, are indicated in red and connected with green lines. Aberrations located to the same chromosomes are circled in gray for visualization purposes.

Mentions: To visualize associations between genomic imbalances we performed multidimensional scaling (MDS) on all recurrent genomic alterations (Figure 2). Moreover, significant associations (Bonferroni corrected p<0.05, hypergeometric tests) were found between 19 combinations of aberrations (Figure 2). These analyses thus highlighted connections between different sets of genomic imbalances. For example, deletions on 9p, 9q, and 11p were connected, whereas 6p22 amplifications were associated with losses on 13q14, 10q, and 20q (Figure 2).


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)

Associations between chromosomal aberrations visualized by MDS.Recurrent FGAs, HDs, and MRDs, as well as recurrent large chromosome arm deletions were included in the analysis. FGAs and HDs present in <5% of samples were excluded. Aberrations with significant positive associations, as determined by hypergeometric tests, are indicated in red and connected with green lines. Aberrations located to the same chromosomes are circled in gray for visualization purposes.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038863-g002: Associations between chromosomal aberrations visualized by MDS.Recurrent FGAs, HDs, and MRDs, as well as recurrent large chromosome arm deletions were included in the analysis. FGAs and HDs present in <5% of samples were excluded. Aberrations with significant positive associations, as determined by hypergeometric tests, are indicated in red and connected with green lines. Aberrations located to the same chromosomes are circled in gray for visualization purposes.
Mentions: To visualize associations between genomic imbalances we performed multidimensional scaling (MDS) on all recurrent genomic alterations (Figure 2). Moreover, significant associations (Bonferroni corrected p<0.05, hypergeometric tests) were found between 19 combinations of aberrations (Figure 2). These analyses thus highlighted connections between different sets of genomic imbalances. For example, deletions on 9p, 9q, and 11p were connected, whereas 6p22 amplifications were associated with losses on 13q14, 10q, and 20q (Figure 2).

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