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Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract.

Miller G, Socci ND, Dhall D, D'Angelica M, DeMatteo RP, Allen PJ, Singh B, Fong Y, Blumgart LH, Klimstra DS, Jarnagin WR - J. Exp. Clin. Cancer Res. (2009)

Bottom Line: Results were confirmed by RT-PCR.Clinical-pathologic correlation was made using functional over-representation analysis of the top 100 mutations associated with each variable.The findings have implications for identification of therapeutic targets, screening, and prognostication.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. george.miller@med.nyu.edu

ABSTRACT

Background: The pathogenesis of biliary cancers is ill-defined. This study investigates changes in gene expression and copy number in biliary cancers and correlates these changes with anatomical site of origin, histopathology and outcome.

Methods: We performed gene expression and CGH analysis on 34 biliary tract cancer specimens. Results were confirmed by RT-PCR. Clinical-pathologic correlation was made using functional over-representation analysis of the top 100 mutations associated with each variable.

Results: There were 545 genes with altered expression in extrahepatic cholangiocarcinoma, 2,354 in intrahepatic cholangiocarcinoma, and 1,281 in gallbladder cancer. Unsupervised hierarchical clustering analysis indicated there was no difference in the global gene expression patterns between each biliary cancer subgroup. CGH analysis revealed that short segments of chromosomes 1p, 3p, 6q, 8p, 9p, and 14q were commonly deleted across all cancer subtypes. Commonly amplified regions included segments of 1q, 3q, 5p, 7p, 7q, 8q, and 20q. Over-representation analysis revealed an association between altered expression of functional gene groupings and pathologic features.

Conclusion: This study defined regions of the genome associated with changes in DNA copy number and gene expression in specific subtypes of biliary cancers. The findings have implications for identification of therapeutic targets, screening, and prognostication.

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Related in: MedlinePlus

Chromosomal Structural Mutations in Biliary Tract Cancers. (a) A cumulative depiction of the copy number changes across the genome for all biliary cancer specimens is shown. Chromosomal number is listed on the left. Amplification is depicted in red and deletion in blue. White is unchanged from genomic DNA controls. Increased amplification or deletion within a cancer specimen is reflected in increased color intensity. The percentage of patient specimens that have either amplifications or deletions at each chromosomal loci is shown for (b) EHC, (c) IHC, (d) GBC, and (e) all biliary tract cancers combined.
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Figure 2: Chromosomal Structural Mutations in Biliary Tract Cancers. (a) A cumulative depiction of the copy number changes across the genome for all biliary cancer specimens is shown. Chromosomal number is listed on the left. Amplification is depicted in red and deletion in blue. White is unchanged from genomic DNA controls. Increased amplification or deletion within a cancer specimen is reflected in increased color intensity. The percentage of patient specimens that have either amplifications or deletions at each chromosomal loci is shown for (b) EHC, (c) IHC, (d) GBC, and (e) all biliary tract cancers combined.

Mentions: To better understand the molecular pathogenesis of biliary tract cancers we used an array based CGH analysis to detect chromosomal areas of DNA copy number gain (DNA copy number of 3 or greater) and loss (DNA copy number of 0 or 1) in the GBC, IHC, and EHC specimens. Figure 2a depicts the chromosomal alterations for each individual cancer specimen while Figure 2b–d represents cumulative summaries of the chromosomal changes for each cancer subtype. Cumulative chromosomal changes for all biliary tract cancers combined are shown in Figure 2e.


Genome wide analysis and clinical correlation of chromosomal and transcriptional mutations in cancers of the biliary tract.

Miller G, Socci ND, Dhall D, D'Angelica M, DeMatteo RP, Allen PJ, Singh B, Fong Y, Blumgart LH, Klimstra DS, Jarnagin WR - J. Exp. Clin. Cancer Res. (2009)

Chromosomal Structural Mutations in Biliary Tract Cancers. (a) A cumulative depiction of the copy number changes across the genome for all biliary cancer specimens is shown. Chromosomal number is listed on the left. Amplification is depicted in red and deletion in blue. White is unchanged from genomic DNA controls. Increased amplification or deletion within a cancer specimen is reflected in increased color intensity. The percentage of patient specimens that have either amplifications or deletions at each chromosomal loci is shown for (b) EHC, (c) IHC, (d) GBC, and (e) all biliary tract cancers combined.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698861&req=5

Figure 2: Chromosomal Structural Mutations in Biliary Tract Cancers. (a) A cumulative depiction of the copy number changes across the genome for all biliary cancer specimens is shown. Chromosomal number is listed on the left. Amplification is depicted in red and deletion in blue. White is unchanged from genomic DNA controls. Increased amplification or deletion within a cancer specimen is reflected in increased color intensity. The percentage of patient specimens that have either amplifications or deletions at each chromosomal loci is shown for (b) EHC, (c) IHC, (d) GBC, and (e) all biliary tract cancers combined.
Mentions: To better understand the molecular pathogenesis of biliary tract cancers we used an array based CGH analysis to detect chromosomal areas of DNA copy number gain (DNA copy number of 3 or greater) and loss (DNA copy number of 0 or 1) in the GBC, IHC, and EHC specimens. Figure 2a depicts the chromosomal alterations for each individual cancer specimen while Figure 2b–d represents cumulative summaries of the chromosomal changes for each cancer subtype. Cumulative chromosomal changes for all biliary tract cancers combined are shown in Figure 2e.

Bottom Line: Results were confirmed by RT-PCR.Clinical-pathologic correlation was made using functional over-representation analysis of the top 100 mutations associated with each variable.The findings have implications for identification of therapeutic targets, screening, and prognostication.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. george.miller@med.nyu.edu

ABSTRACT

Background: The pathogenesis of biliary cancers is ill-defined. This study investigates changes in gene expression and copy number in biliary cancers and correlates these changes with anatomical site of origin, histopathology and outcome.

Methods: We performed gene expression and CGH analysis on 34 biliary tract cancer specimens. Results were confirmed by RT-PCR. Clinical-pathologic correlation was made using functional over-representation analysis of the top 100 mutations associated with each variable.

Results: There were 545 genes with altered expression in extrahepatic cholangiocarcinoma, 2,354 in intrahepatic cholangiocarcinoma, and 1,281 in gallbladder cancer. Unsupervised hierarchical clustering analysis indicated there was no difference in the global gene expression patterns between each biliary cancer subgroup. CGH analysis revealed that short segments of chromosomes 1p, 3p, 6q, 8p, 9p, and 14q were commonly deleted across all cancer subtypes. Commonly amplified regions included segments of 1q, 3q, 5p, 7p, 7q, 8q, and 20q. Over-representation analysis revealed an association between altered expression of functional gene groupings and pathologic features.

Conclusion: This study defined regions of the genome associated with changes in DNA copy number and gene expression in specific subtypes of biliary cancers. The findings have implications for identification of therapeutic targets, screening, and prognostication.

Show MeSH
Related in: MedlinePlus