Comprehensive Profiling of 8p11-12 Amplification in Breast Cancer

Abstract

In human carcinomas, especially breast cancer, chromosome arm 8p is frequently involved in complex chromosomal rearrangements that combine amplification at 8p11-12, break in the 8p12-21 region, and loss of 8p21-ter. Several studies have identified putative oncogenes in the 8p11-12 amplicon. However, discrepancies and the lack of knowledge on the structure of this amplification lead us to think that the actual identity of the oncogenes is not definitively established. We present here a comprehensive study combining genomic, expression, and chromosome break analyses of the 8p11-12 region in breast cell lines and primary breast tumors. We show the existence of four amplicons at 8p11-12 using array comparative genomic hybridization. Gene expression analysis of 123 samples using DNA microarrays identified 14 genes significantly overexpressed in relation to amplification. Using fluorescence in situ hybridization analysis on tissue microarrays, we show the existence of a cluster of breakpoints spanning a region just telomeric to and associated with the amplification. Finally, we show that 8p11-12 amplification has a pejorative effect on survival in breast cancer. (Mol Cancer Res 2005;3(12):655 -67)

A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines

“…For instance, in agreement with previous studies [40,41], on 8p11.2-q12.1, 4 smallest regions of amplification (SRAs) were identified, whereas on 20q13, at least three distinct SRAs were found. It should be noted, however, that the results of our study suggest that the SRA of each amplicon in breast cancer cell lines is larger than that found in human cancers (e.g., the 17q12-q21 SRA in this study spanned the region from 32.33 to 35.69 Mb, whereas in a previous study using the same platform, we have demonstrated that the 17q12-q21 SRA in primary breast cancers spans 414 kb) [18].…”

“…The high resolution of the aCGH platform employed here has confirmed the structural complexity of amplicons found in breast cancer cell lines and primary breast cancers [40,41,57]. For instance, in agreement with previous studies [40,41], on 8p11.2-q12.1, 4 smallest regions of amplification (SRAs) were identified, whereas on 20q13, at least three distinct SRAs were found.…”

“…Recent studies have demonstrated that amplicons often have more than one driver [16,31,[39][40][41]. Previous studies have demonstrated that expression of genes consistently overexpressed when amplified may be required for the survival of cells harbouring amplification of their genetic loci [31,39,42,43].…”

Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q

“…Interestingly, gains at 1q were of low-to-moderate level with a lower prevalence of amplifications compared to other chromosomes. Furthermore, no sharp transitions were observed at the boundaries of amplification peaks at 1q, in contrast to chromosomes 8p or 17q, where such recurrent breakpoint sites were common (Orsetti et al, 2004;Gelsi-Boyer et al, 2005).…”

“…Coverage of chromosomes 8 and 17 has been described by Orsetti et al (2004) and Gelsi-Boyer et al (2005). Chromosome 1 was covered by 257 BAC clones selected as follows: 225 BAC clones from the Barbara Trask collection (CHORI) http://www.ncbi.nlm.…”