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.
Miller
George
G
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. george.miller@med.nyu.edu
Socci
Nicholas D
ND
Dhall
Deepti
D
D'Angelica
Michael
M
DeMatteo
Ronald P
RP
Allen
Peter J
PJ
Singh
Bhuvanesh
B
Fong
Yuman
Y
Blumgart
Leslie H
LH
Klimstra
David S
DS
Jarnagin
William R
WR
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