Novel patterns of genome rearrangement and their association with survival in breast cancer

Abstract

Representational Oligonucleotide Microarray Analysis (ROMA) detects genomic amplifications and deletions with boundaries defined at a resolution of ∼50 kb. We have used this technique to examine 243 breast tumors from two separate studies for which detailed clinical data were available. The very high resolution of this technology has enabled us to identify three characteristic patterns of genomic copy number variation in diploid tumors and to measure correlations with patient survival. One of these patterns is characterized by multiple closely spaced amplicons, or “firestorms,” limited to single chromosome arms. These multiple amplifications are highly correlated with aggressive disease and poor survival even when the rest of the genome is relatively quiet. Analysis of a selected subset of clinical material suggests that a simple genomic calculation, based on the number and proximity of genomic alterations, correlates with life-table estimates of the probability of overall survival in patients with primary breast cancer. Based on this sample, we generate the working hypothesis that copy number profiling might provide information useful in making clinical decisions, especially regarding the use or not of systemic therapies (hormonal therapy, chemotherapy), in the management of operable primary breast cancer with ostensibly good prognosis, for example, small, node-negative, hormone-receptor-positive diploid cases.

Genomic and immunohistochemical analysis of adenosquamous carcinoma of the breast

“…Microarray comparative genomic hybridization analysis of case 2 revealed gains of 7p-q11.21, encompassing the centromere and a high-level Figure 4 Genome plots and chromosome 7 plots of case 1 (a and c) and case 2 (b and d). Case 1 displayed a rather simple pattern of genomic aberrations, whereas case 2 showed a greater complexity, with a complex firestorm pattern, 22 with two regions of high-level amplification in chromosome 7, one of which encompassed the EGFR gene locus. In the genome plots (a and b), CBS (circular binary segmentation) log 2 ratios are plotted on the y axis against each clone according to genomic location on the x axis.…”

“…( Figure 4b and b). Its genomic profile was characterized by a complex 'firestorm' pattern, 22 with two amplification peaks on chromosome 7. Gains of 1q, 5q, 7p, 8q, 12p, 14q, 16p, 16q and 18pq, losses of 1p, 3q, 8p, 9p, 12q, 17p, 17q, 22q and Xpq, and high-level amplification of 7p11.2, encompassing the EGFR gene, and 7q11.21 were observed.…”

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

“…Genome architecture patterns were essentially determined as described by Hicks et al [24]. Cases were considered of 'simplex' pattern if their genomic profiles were characterised by broad segments of duplication and deletion, usually comprising entire chromosomes or chromosomal arms.…”

“…Cases were considered of 'simplex' pattern if their genomic profiles were characterised by broad segments of duplication and deletion, usually comprising entire chromosomes or chromosomal arms. Complex patterns included 'sawtooth' and 'firestorm' [24]. Cases with a 'sawtooth' profile were characterised by many narrow segments of duplication and deletion, often alternating and affecting most if not all chromosomes.…”

Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis

“…4a). Loss of 16q is one of the most common observed copy number aberrations in breast cancer [23] and has previously been associated with good prognosis in three studies using LOH [24], gene expression profiling [25], or aCGH [26].…”