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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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Validation of gene expression data by IHC on tissue microarray.A) Barplots summarizing tumor cell protein scores of selected proteins in tumors stratified according to the gene expression subtypes. Error bars represent ±SEM. B) IHC stainings of two representative HC1 (top) and HC5 samples (bottom).
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pone-0038863-g005: Validation of gene expression data by IHC on tissue microarray.A) Barplots summarizing tumor cell protein scores of selected proteins in tumors stratified according to the gene expression subtypes. Error bars represent ±SEM. B) IHC stainings of two representative HC1 (top) and HC5 samples (bottom).

Mentions: The above analysis led us to refine the subgrouping of tumors into groups that share central features of gene expression, genomic alterations, and gene mutation data (Figure 4C). Two of the groups, HC1 and HC2a/HC3a, respectively, were highly enriched for FGFR3 mutations, high CCND1 expression, and 9q deletions. However, for HC2a/HC3a tumors the frequency of CDKN2A deletions was drastically increased, suggesting that acquisition of CDKN2A deletions occurs later during tumor progression than for example FGFR3 mutations and 9q deletions. The tumors in HC3c and HC5 did, on the other hand, seem to depend on alternative genomic and genetic alterations as suggested by the high incidence of 6p22 amplifications and RB1 deletions, and the near absence of both FGFR3 mutations and CDKN2A deletions (Figure 4C). These observations were substantiated by immunohistochemical analysis of FGFR3, CCND1, p16, E2F3, and RB1 protein expression in 119 matched samples using TMA (Figure 5A). Protein expression of these markers for two representative samples of the HC1 and HC5 subgroups, respectively, is illustrated in Figure 5B.


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)

Validation of gene expression data by IHC on tissue microarray.A) Barplots summarizing tumor cell protein scores of selected proteins in tumors stratified according to the gene expression subtypes. Error bars represent ±SEM. B) IHC stainings of two representative HC1 (top) and HC5 samples (bottom).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038863-g005: Validation of gene expression data by IHC on tissue microarray.A) Barplots summarizing tumor cell protein scores of selected proteins in tumors stratified according to the gene expression subtypes. Error bars represent ±SEM. B) IHC stainings of two representative HC1 (top) and HC5 samples (bottom).
Mentions: The above analysis led us to refine the subgrouping of tumors into groups that share central features of gene expression, genomic alterations, and gene mutation data (Figure 4C). Two of the groups, HC1 and HC2a/HC3a, respectively, were highly enriched for FGFR3 mutations, high CCND1 expression, and 9q deletions. However, for HC2a/HC3a tumors the frequency of CDKN2A deletions was drastically increased, suggesting that acquisition of CDKN2A deletions occurs later during tumor progression than for example FGFR3 mutations and 9q deletions. The tumors in HC3c and HC5 did, on the other hand, seem to depend on alternative genomic and genetic alterations as suggested by the high incidence of 6p22 amplifications and RB1 deletions, and the near absence of both FGFR3 mutations and CDKN2A deletions (Figure 4C). These observations were substantiated by immunohistochemical analysis of FGFR3, CCND1, p16, E2F3, and RB1 protein expression in 119 matched samples using TMA (Figure 5A). Protein expression of these markers for two representative samples of the HC1 and HC5 subgroups, respectively, is illustrated in Figure 5B.

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