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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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Integrated analysis of genomic alterations, gene mutations, and gene expression data.A) Recurrent genomic alterations with significant association to gene expression subtypes. Activating mutation of FGFR3, PIK3CA, and RAS, and inactivating mutations of CDKN2A, as well as amplifications of FGFR3 and RAF1, and TP53/MDM2 status is also displayed. Within each HCA group, samples are ordered according to their relative FGFR3 expression. Dashed vertical lines, which define subsets within each HCA group, are drawn with respect to the E2F3, RB1, 5p, RAF1, and RAS alterations pattern and FGFR3 expression. Amplifications and homozygous deletions are indicated in black. Gains and deletions are indicated in gray. Activating/inactivating mutations are indicated in black. B) Heatmap representing relative expression levels of selected genes and the Bild E2F3 signature [17]. Green, low expression; red high expression. C) Frequencies of selected genomic alterations in gene expression subgroups.
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pone-0038863-g004: Integrated analysis of genomic alterations, gene mutations, and gene expression data.A) Recurrent genomic alterations with significant association to gene expression subtypes. Activating mutation of FGFR3, PIK3CA, and RAS, and inactivating mutations of CDKN2A, as well as amplifications of FGFR3 and RAF1, and TP53/MDM2 status is also displayed. Within each HCA group, samples are ordered according to their relative FGFR3 expression. Dashed vertical lines, which define subsets within each HCA group, are drawn with respect to the E2F3, RB1, 5p, RAF1, and RAS alterations pattern and FGFR3 expression. Amplifications and homozygous deletions are indicated in black. Gains and deletions are indicated in gray. Activating/inactivating mutations are indicated in black. B) Heatmap representing relative expression levels of selected genes and the Bild E2F3 signature [17]. Green, low expression; red high expression. C) Frequencies of selected genomic alterations in gene expression subgroups.

Mentions: The results presented in Figure 2 suggested that two separate branches of interconnected genomic alterations may be present in UCs. To explore this finding further, we identified recurrent genomic aberrations that were significantly associated (Bonferroni corrected p<0.05, Fisher's tests) with the five gene expression subgroups shown in Figure 3A. Ten focal events (FGAs, HDs or MRDs) and six large chromosome arm alterations were significantly associated with specific HCA groups (Figure 4A). The most common chromosomal alteration in HC1 was deletions on whole or large segments of 9q (50%). HC2 tumors showed frequent losses on both 9p and 9q, and a high frequency (65%) of hemizygous/homozygous CDKN2A deletions. HC1 and HC2 also displayed a high prevalence of FGFR3 and PIK3CA mutations (Figure 4A), and consistent high FGFR3 and CCND1 expression (Figure 4B). However, genomic amplifications of CCND1 were associated with HC4 (7 of 17 HC4 cases; Figure 4A).


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)

Integrated analysis of genomic alterations, gene mutations, and gene expression data.A) Recurrent genomic alterations with significant association to gene expression subtypes. Activating mutation of FGFR3, PIK3CA, and RAS, and inactivating mutations of CDKN2A, as well as amplifications of FGFR3 and RAF1, and TP53/MDM2 status is also displayed. Within each HCA group, samples are ordered according to their relative FGFR3 expression. Dashed vertical lines, which define subsets within each HCA group, are drawn with respect to the E2F3, RB1, 5p, RAF1, and RAS alterations pattern and FGFR3 expression. Amplifications and homozygous deletions are indicated in black. Gains and deletions are indicated in gray. Activating/inactivating mutations are indicated in black. B) Heatmap representing relative expression levels of selected genes and the Bild E2F3 signature [17]. Green, low expression; red high expression. C) Frequencies of selected genomic alterations in gene expression subgroups.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038863-g004: Integrated analysis of genomic alterations, gene mutations, and gene expression data.A) Recurrent genomic alterations with significant association to gene expression subtypes. Activating mutation of FGFR3, PIK3CA, and RAS, and inactivating mutations of CDKN2A, as well as amplifications of FGFR3 and RAF1, and TP53/MDM2 status is also displayed. Within each HCA group, samples are ordered according to their relative FGFR3 expression. Dashed vertical lines, which define subsets within each HCA group, are drawn with respect to the E2F3, RB1, 5p, RAF1, and RAS alterations pattern and FGFR3 expression. Amplifications and homozygous deletions are indicated in black. Gains and deletions are indicated in gray. Activating/inactivating mutations are indicated in black. B) Heatmap representing relative expression levels of selected genes and the Bild E2F3 signature [17]. Green, low expression; red high expression. C) Frequencies of selected genomic alterations in gene expression subgroups.
Mentions: The results presented in Figure 2 suggested that two separate branches of interconnected genomic alterations may be present in UCs. To explore this finding further, we identified recurrent genomic aberrations that were significantly associated (Bonferroni corrected p<0.05, Fisher's tests) with the five gene expression subgroups shown in Figure 3A. Ten focal events (FGAs, HDs or MRDs) and six large chromosome arm alterations were significantly associated with specific HCA groups (Figure 4A). The most common chromosomal alteration in HC1 was deletions on whole or large segments of 9q (50%). HC2 tumors showed frequent losses on both 9p and 9q, and a high frequency (65%) of hemizygous/homozygous CDKN2A deletions. HC1 and HC2 also displayed a high prevalence of FGFR3 and PIK3CA mutations (Figure 4A), and consistent high FGFR3 and CCND1 expression (Figure 4B). However, genomic amplifications of CCND1 were associated with HC4 (7 of 17 HC4 cases; Figure 4A).

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