Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene‐expression subtypes of breast cancer

Abstract

Breast cancer is a leading cause of cancer-death among women, where the clinicopathological features of tumors are used to prognosticate and guide therapy. DNA copy number alterations (CNAs), which occur frequently in breast cancer and define key pathogenetic events, are also potentially useful prognostic or predictive factors. Here, we report a genome-wide array-based comparative genomic hybridization (array CGH) survey of CNAs in 89 breast tumors from a patient cohort with locally advanced disease. Statistical analysis links distinct cytoband loci harboring CNAs to specific clinicopathological parameters, including tumor grade, estrogen receptor status, presence of TP53 mutation, and overall survival. Notably, distinct spectra of CNAs also underlie the different subtypes of breast cancer recently defined by expression-profiling, implying these subtypes develop along distinct genetic pathways. In addition, higher numbers of gains/losses are associated with the "basal-like" tumor subtype, while high-level DNA amplification is more frequent in "luminal-B" subtype tumors, suggesting also that distinct mechanisms of genomic instability might underlie their pathogenesis. The identified CNAs may provide a basis for improved patient prognostication, as well as a starting point to define important genes to further our understanding of the pathobiology of breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

“…Luminal A tumors frequently have þ 1q, þ 16p, À11q23 and À16q; luminal B tumors show genomic aberrations of other regions such as À8p, þ 8q, þ 20q and À22q. These subtype-GAPs and the recurrent chromosomal aberrations within each subtype are in agreement with those previously reported in SBC (Supplementary Table 2) (Bergamaschi et al, 2006;Chin et al, 2006). …”

“…We have studied the genomic change features of the five FBC subtypes using array-CGH data from a previous analysis (Melchor et al, in press). Basal-like tumors showed the highest genomic instability (Figure 2), consistent with two previous studies in SBC (Bergamaschi et al, 2006;Chin et al, 2006). In contrast, luminal A tumors had the lowest number of genomic aberrations.…”

“…In contrast, luminal A tumors had the lowest number of genomic aberrations. Bergamaschi et al (2006) found the lowest number in ERBB2 tumors, but the low number of ERBB2 samples in our study (four cases) did not allow us to draw any significant conclusions. The FBC subtypes defined by IHC exhibited distinct GAP (Figure 3).…”

“…Distinct genomic aberration patterns associated with each FBC subtype Different genomic characteristics have been recently associated with each of the five subtypes of SBC (Bergamaschi et al, 2006;Chin et al, 2006). We have studied the genomic change features of the five FBC subtypes using array-CGH data from a previous analysis (Melchor et al, in press).…”

“…Recently, two different studies have described distinct spectra of DNA copy number alterations associated with each SBC subtype. A higher number of gains/losses were associated with basal-like tumors, while high-level DNA amplification was more frequent in luminal-B subtype tumors (Bergamaschi et al, 2006;Chin et al, 2006).…”