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


CONCLUSIONS
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.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. george.miller@med.nyu.edu
George
G
Miller
Nicholas D
ND
Socci
Deepti
D
Dhall
Michael
M
D'Angelica
Ronald P
RP
DeMatteo
Peter J
PJ
Allen
Bhuvanesh
B
Singh
Yuman
Y
Fong
Leslie H
LH
Blumgart
David S
DS
Klimstra
William R
WR
Jarnagin
D000368:Aged; D000369:Aged, 80 and over; D001661:Biliary Tract Neoplasms / Q000235:genetics* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm