A 1 Mb minimal amplicon at 8p11–12 in breast cancer identifies new candidate oncogenes

Abstract

Amplification of 8p11-12 is a well-known alteration in human breast cancers but the driving oncogene has not been identified. We have developed a high-resolution comparative genomic hybridization array covering 8p11-12 and analysed 33 primary breast tumors, 20 primary ovarian tumors and 27 breast cancer cell lines. Expression analysis of the genes in the region was carried out by using real-time quantitative PCR and/or oligo-microarray profiling. In all, 24% (8/33) of the breast tumors, 5% (1/20) of the ovary tumors and 15% (4/27) of the cell lines showed 8p11-12 amplification. We identified a 1 Mb segment of common amplification that excludes previously proposed candidate genes. Some of the amplified genes did not show overexpression, whereas for others, overexpression was not specifically attributable to amplification. The genes FLJ14299, C8orf2, BRF2 and RAB11FIP, map within the 8p11-12 minimal amplicon, two have a putative function consistent with an oncogenic role, these four genes showed a strong correlation between amplification and overexpression and are therefore the best candidate driver oncogenes at 8p12.

High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation

“…Several (Cama-1, HCC1500, MDA-MB-134, MDA-MB-175, MDA-MB-361, SUIT-2, SUM44, SUM52 and ZR-75-1) show at least low-level amplification of a fragment immediately proximal to the main break. All of these, except Cama-1, have been reported before (Lemieux et al, 1996;Courtay-Cahen et al, 2000;Adelaide et al, 2003;Ray et al, 2004;Garcia et al, 2005) and all, except those in Cama-1 and the SUM lines, have been verified by us using FISH with BACs and chromosome 8 paint. HCC38 and UACC812 have a small amplicon substantially proximal to the main break, and two BACs spanning the FGFR1 locus are amplified in HCC1599.…”

“…The ZNF703/FLJ14299, SPFH2, BRF2 and RAB11FIP1 genes map to this region and their amplification correlates with overexpression. This amplicon was present in 24% of primary breast tumours and found to correlate with poor survival (Garcia et al, 2005;Prentice et al, 2005). The long-suspected amplification target, FGFR1, was excluded from the current consensus amplicon and detected as amplified in fewer, 10-15%, of cases (Theillet et al, 1993;Ugolini et al, 1999;Prentice et al, 2005).…”

“…Davidson et al, 2000;AbdelRahman et al, 2001;Karan et al, 2003;Hurst et al, 2004;Hwang et al, 2004), and more recently array CGH has begun to provide more detail of these losses (e.g. Paris et al, 2003;Douglas et al, 2004;Hurst et al, 2004;Nakao et al, 2004;Garcia et al, 2005). Distal 8p also frequently shows loss of heterozygosity (LOH), which would often reflect loss through unbalanced translocation (for references see Adams et al, 2005).…”

“…large-scale amplifications) attached to 8p12 (Bernardino et al, 1998) and fluorescence in situ hybridization (FISH), CGH and Southern blotting show amplification generally in the region of 8p12 (Dib et al, 1995;Bautista and Theillet, 1998;Davidson et al, 2000), which often, but not invariably, includes FGFR1, and may occasionally extend as far distally as NRG1 (Ugolini et al, 1999). Recent array CGH studies that examine the 8p12 region in breast cancer have concentrated on the definition of the 8p12 amplicon (Ray et al, 2004;Garcia et al, 2005;Prentice et al, 2005). The amplicon has been defined to extend from 36.9 to 37.9 Mb (Garcia et al, 2005).…”

“…Recent array CGH studies that examine the 8p12 region in breast cancer have concentrated on the definition of the 8p12 amplicon (Ray et al, 2004;Garcia et al, 2005;Prentice et al, 2005). The amplicon has been defined to extend from 36.9 to 37.9 Mb (Garcia et al, 2005). The ZNF703/FLJ14299, SPFH2, BRF2 and RAB11FIP1 genes map to this region and their amplification correlates with overexpression.…”