Distinct Chromosomal Bias of Gene Expression Signatures in the Progression of Hepatocellular Carcinoma

Abstract

To identify the chromosomal aberrations associated with the progression of liver cancer, we applied expression imbalance map analysis to gene expression data from 31 hepatocellular carcinomas and 19 noncancerous tissues. Expression imbalance map analysis, which detects mRNA expression imbalance correlated with chromosomal regions, showed that expression gains of 1q21-23 (74%), 8q13-21 (48%), 12q23-24 (41%), 17q12-21(48%), 17q25 (25%), and 20q11 (22%) and losses of 4q13 (48%), 8p12-21 (32%), 13q14 (32%), and 17p13 (29%) were significantly associated with hepatocellular carcinoma. Most regions with altered expression identified by expression imbalance map were also identified in previous reports using comparative genomic hybridization. We demonstrated chromosomal copy number gain in 1q21-23 and loss in 17p13 by genomic quantitative PCR, suggesting that gene expression profiles reflect chromosomal alterations. Furthermore, expression imbalance map analysis revealed that more poorly differentiated hepatocellular carcinoma contain more chromosomal alterations, which are accumulated in a stepwise manner in the course of hepatocellular carcinoma progression: expression imbalance of 1q, 8p, 8q, and 17p occur as early events in hepatocarcinogenesis, and 12q, 17q25 and 20q occur as later events. In particular, expression gain of 17q12-21 and loss of 4q were seen to accumulate constantly through the dedifferentiation process. Our data suggest that gene expression profiles are subject to chromosomal bias and that expression imbalance map can correlate gene expression to gene loci with high resolution and sensitivity.

Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays

“…We demonstrated the robustness of GIM analysis based on genotyping arrays in the accurate analysis of copy number alterations and allelic imbalance in the cancer genome in a single experiment. Furthermore, by integrating the gene expression data with genomic alterations, we have demonstrated that genomic alterations are reflected in the gene expression profile (Kano et al, 2003;Midorikawa et al, 2004). Our results confirmed a positive correlation between genome dosage and transcription.…”

“…To confirm these observations, the effects of genome imbalance on the transcriptome were validated by direct comparison with expression data from the same samples in the present study. Previously, we also demonstrated stepwise chromosomal expression changes in the progression of HCC (Midorikawa et al, 2004), that is, expression gain in 1q and 8p, and loss of 8p, 13q and 17p were observed in well-differentiated liver cancer, whereas expression gains in 12q, 17q and 20q, and reduction in 4q were demonstrated only in advanced HCC. On the other hand, GIM showed frequent allelic gains at 1q, 5q, 6p and 8q, and LOH at 8p and 16q regardless of cancer differentiation grade, and gains at 12q and LOH at 15q were detected specifically in poorly differentiated tumors.…”

“…We and other groups reported previously that genome dosage reflects expression imbalance (Pollack et al, Genome-wide analysis of DNA copy number in hepatocellular carcinoma Y Midorikawa et al 2002; Midorikawa et al, 2004). Upender et al (2004) demonstrated that genomic aneuploidy affects gene expression pattern using the chromosome transfer model.…”

Jagged1 DNA Copy Number Variation Is Associated with Poor Outcome in Liver Cancer

“…A previous report showed genomic alterations in liver cancer using CGH analyses and frequent gains were observed in 1q, 6p, 8q, and 17q, whereas losses were observed in 4q, 8p, 13q, 16q, and 17p. In addition to these gained locations, 20p11 was also present in some liver cancer tissue 18 . Moreover, five BAC clones for this experiment were found listed in BAC array CGH, but only Jagged1 gene was a candidate because the different expression patterns were associated with the AFP-producing status of hepatoma cells using microarray.…”

Aberrant expression of RAB1A in human tongue cancer

“…Pajunen et al (1987Pajunen et al ( , 1988 assigned the gene to chromosome 17, specifically, 17q23 -q25. The chromosomal aberration of this region may be involved in carcinogenesis in the tylosis with oesophageal cancer (TOC) (Shahabi et al, 2004) and liver cancer (Midorikawa et al, 2004).…”