Stage-specific alterations of the genome, transcriptome, and proteome during colorectal carcinogenesis.
To identify sequential alterations of the genome, transcriptome, and proteome during colorectal cancer progression, we have analyzed tissue samples from 36 patients, including the complete mucosa-adenoma-carcinoma sequence from 8 patients. Comparative genomic hybridization (CGH) revealed patterns of stage specific, recurrent genomic imbalances. Gene expression analysis on 9K cDNA arrays identified 58 genes differentially expressed between normal mucosa and adenoma, 116 genes between adenoma and carcinoma, and 158 genes between primary carcinoma and liver metastasis (P < 0.001). Parallel analysis of our samples by CGH and expression profiling revealed a direct correlation of chromosomal copy number changes with chromosome-specific average gene expression levels. Protein expression was analyzed by two-dimensional gel electrophoresis and subsequent mass spectrometry. Although there was no direct match of differentially expressed proteins and genes, the majority of them belonged to identical pathways or networks. In conclusion, increasing genomic instability and a recurrent pattern of chromosomal imbalances as well as specific gene and protein expression changes correlate with distinct stages of colorectal cancer progression. Chromosomal aneuploidies directly affect average resident gene expression levels, thereby contributing to a massive deregulation of the cellular transcriptome. The identification of novel genes and proteins might deliver molecular targets for diagnostic and therapeutic interventions.
Habermann
Jens K
JK
Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892-8010, USA. habermaj@mail.nih.gov
Paulsen
Ulrike
U
Roblick
Uwe J
UJ
Upender
Madhvi B
MB
McShane
Lisa M
LM
Korn
Edward L
EL
Wangsa
Danny
D
Krüger
Stefan
S
Duchrow
Michael
M
Bruch
Hans-Peter
HP
Auer
Gert
G
Ried
Thomas
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D020543:Proteome