Stage‐specific alterations of the genome, transcriptome, and proteome during colorectal carcinogenesis

Abstract

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.

Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma

“…These aberrations are faithfully conserved in carcinomas and are accompanied by gains of chromosomes and chromosomal arms 6, 8q, and 20, as well as losses of 4q, 8p, 17p, and 18q. 6 We could further show that introduction of trisomic chromosomes in an otherwise diploid genome increases the average gene expression level of the resident genes independent of cell type or chromosome. 11 This effect was validated in a clinical cohort of colorectal carcinomas in which we could identify a correlation between chromosome amplifications and increased expression levels of the genes resident on the affected chromosomes.…”

“…5 Cytogenetic and molecular cytogenetic analyses have revealed that tumor-specific gains and losses of entire chromosomes or chromosome arms are early genome mutations. [6][7][8][9] The genomic imbalances show a strikingly conserved recurrent pattern that is characteristic for colorectal carcinomas and is distinct from other solid tumors. 6 For a comprehensive overview, please see http://cgap.…”

“…[6][7][8][9] The genomic imbalances show a strikingly conserved recurrent pattern that is characteristic for colorectal carcinomas and is distinct from other solid tumors. 6 For a comprehensive overview, please see http://cgap. nci.nih.gov/Chromosomes/Mitelman.…”

“…11 This effect was validated in a clinical cohort of colorectal carcinomas in which we could identify a correlation between chromosome amplifications and increased expression levels of the genes resident on the affected chromosomes. 6 Therefore, it seems reasonable to assume that genes located on chromosomes that are affected by amplification or deletion do have an important role for colorectal carcinogenesis.…”

Cancer: A proteomic disease

“…Habermann et al [13] analyzed the sequential alterations of the genome, transcriptome, and proteome during colorectal cancer progression and found that the expression of nine proteins decreased, and 32 proteins increased in proportion to cancer malignancy. The proteins identified played a role in cell cycle regulation, apoptosis and signal transduction ( Figure 1).…”