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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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Genomic networks and survival analysis of genomic subtypes.A) MDS plot based on the subset of genomic alterations (Figure 4A) and categorized gene expression data (Figure S3B) that showed at least one instance of significant positive or negative association in a pair-wise hypergeometric tests. Green lines, significant positive association; red lines, significant negative association. B) Kaplan-Meier analysis of tumors grouped according to a combination of gene expression and genomic alteration patterns using disease specific survival (DSS) as endpoint.
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pone-0038863-g006: Genomic networks and survival analysis of genomic subtypes.A) MDS plot based on the subset of genomic alterations (Figure 4A) and categorized gene expression data (Figure S3B) that showed at least one instance of significant positive or negative association in a pair-wise hypergeometric tests. Green lines, significant positive association; red lines, significant negative association. B) Kaplan-Meier analysis of tumors grouped according to a combination of gene expression and genomic alteration patterns using disease specific survival (DSS) as endpoint.

Mentions: The skewed distribution of genetic and genomic alterations between UC subgroups indicated the presence of at least two, possibly three, genomic circuits in UC. To test this more rigorously we performed pairwise hypergeometric tests between all aberrations that were associated with gene expression subclusters. Furthermore, to be able to include gene expression in this analysis, FGFR3 expression were categorized in to high, intermediate, and low expression, and CCND1, RB1, PTEN, CDKN2A, and RAF1 into low and high expression (Figure S4B). In Figure 6A the results are given in the form of a simplified network model. This analysis identified FGFR3 mutations and elevated FGFR3 expression, high CCND1 expression, CDKN2A deletions, and deletion 9q as one circuit (the FGFR3/CCND1 circuit). The other circuit, the E2F3/RB1 circuit, was defined by 6p22 amplifications, deletions of RB1, PTEN, 5q, 2q36, 22q, and 16q, and gains of 5p, accompanied by reduced expression of FGFR3, RB1, and PTEN, and high expression of CDKN2A. The analysis also suggested the presence of a RAF1/RAS route, complementary to FGFR3 mutations; however, this circuit did not attain statistical significance, possibly due the relative low frequency of these alterations.


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)

Genomic networks and survival analysis of genomic subtypes.A) MDS plot based on the subset of genomic alterations (Figure 4A) and categorized gene expression data (Figure S3B) that showed at least one instance of significant positive or negative association in a pair-wise hypergeometric tests. Green lines, significant positive association; red lines, significant negative association. B) Kaplan-Meier analysis of tumors grouped according to a combination of gene expression and genomic alteration patterns using disease specific survival (DSS) as endpoint.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038863-g006: Genomic networks and survival analysis of genomic subtypes.A) MDS plot based on the subset of genomic alterations (Figure 4A) and categorized gene expression data (Figure S3B) that showed at least one instance of significant positive or negative association in a pair-wise hypergeometric tests. Green lines, significant positive association; red lines, significant negative association. B) Kaplan-Meier analysis of tumors grouped according to a combination of gene expression and genomic alteration patterns using disease specific survival (DSS) as endpoint.
Mentions: The skewed distribution of genetic and genomic alterations between UC subgroups indicated the presence of at least two, possibly three, genomic circuits in UC. To test this more rigorously we performed pairwise hypergeometric tests between all aberrations that were associated with gene expression subclusters. Furthermore, to be able to include gene expression in this analysis, FGFR3 expression were categorized in to high, intermediate, and low expression, and CCND1, RB1, PTEN, CDKN2A, and RAF1 into low and high expression (Figure S4B). In Figure 6A the results are given in the form of a simplified network model. This analysis identified FGFR3 mutations and elevated FGFR3 expression, high CCND1 expression, CDKN2A deletions, and deletion 9q as one circuit (the FGFR3/CCND1 circuit). The other circuit, the E2F3/RB1 circuit, was defined by 6p22 amplifications, deletions of RB1, PTEN, 5q, 2q36, 22q, and 16q, and gains of 5p, accompanied by reduced expression of FGFR3, RB1, and PTEN, and high expression of CDKN2A. The analysis also suggested the presence of a RAF1/RAS route, complementary to FGFR3 mutations; however, this circuit did not attain statistical significance, possibly due the relative low frequency of these alterations.

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