Array comparative genomic hybridisation (aCGH) analysis of premenopausal breast cancers from a nuclear fallout area and matched cases from Western New York

Abstract

High-resolution array comparative genomic hybridisation (aCGH) analysis of DNA copy number aberrations (CNAs) was performed on breast carcinomas in premenopausal women from Western New York (WNY) and from Gomel, Belarus, an area exposed to fallout from the 1986 Chernobyl nuclear accident. Genomic DNA was isolated from 47 frozen tumour specimens from 42 patients and hybridised to arrays spotted with more than 3000 BAC clones. In all, 20 samples were from WNY and 27 were from Belarus. In total, 34 samples were primary tumours and 13 were lymph node metastases, including five matched pairs from Gomel. The average number of total CNAs per sample was 76 (range 35 -134). We identified 152 CNAs (92 gains and 60 losses) occurring in more than 10% of the samples. The most common amplifications included gains at 8q13.2 (49%), at 1p21.1 (36%), and at 8q24.21 (36%). The most common deletions were at 1p36.22 (26%), at 17p13.2 (26%), and at 8p23.3 (23%). Belarussian tumours had more amplifications and fewer deletions than WNY breast cancers. HER2/neu negativity and younger age were also associated with a higher number of gains and fewer losses. In the five paired samples, we observed more discordant than concordant DNA changes. Unsupervised hierarchical cluster analysis revealed two distinct groups of tumours: one comprised predominantly of Belarussian carcinomas and the other largely consisting of WNY cases. In total, 50 CNAs occurred significantly more commonly in one cohort vs the other, and these included some candidate signature amplifications in the breast cancers in women exposed to significant radiation. In conclusion, our high-density aCGH study has revealed a large number of genetic aberrations in individual premenopausal breast cancer specimens, some of which had not been reported before. We identified a distinct CNA profile for carcinomas from a nuclear fallout area, suggesting a possible molecular fingerprint of radiation-associated breast cancer.

Association of chromosome band 8q22 copy number gain with high grade invasive breast carcinomas by assessment of core needle biopsies

“…However, while some of these studies did not differentiate between Grade 1, Grade 2, and Grade 3 tumors (Loo et al, 2004;Naylor et al, 2005;Nessling et al, 2005;Varma et al, 2005;Bergamaschi et al, 2006;Fridlyand et al, 2006), other studies performed array CGH using clone sets that did not contain DNA sequence representation within 5 Mb of RP11-10G10 (Somiari et al, 2004;Callagy et al, 2005;Chin et al, 2007). The report of Pierga and colleagues included no Grade 1 tumors, while the report of Stange and colleagues included only two Grade 1 tumors (Stange et al, 2006;Pierga et al, 2007).…”

“…More recent studies have explored genome copy number alterations in invasive breast carcinomas using array-based CGH in relation to tumor pathology, and would therefore have the potential to validate association of 8q22 gains with Grade 3 tumors (Loo et al, 2004;Somiari et al, 2004;Callagy et al, 2005;Naylor et al, 2005;Nessling et al, 2005;Varma et al, 2005;Bergamaschi et al, 2006;Chin et al, 2006Chin et al, , 2007Fridlyand et al, 2006;Stange et al, 2006;Pierga et al, 2007). However, while some of these studies did not differentiate between Grade 1, Grade 2, and Grade 3 tumors (Loo et al, 2004;Naylor et al, 2005;Nessling et al, 2005;Varma et al, 2005;Bergamaschi et al, 2006;Fridlyand et al, 2006), other studies performed array CGH using clone sets that did not contain DNA sequence representation within 5 Mb of RP11-10G10 (Somiari et al, 2004;Callagy et al, 2005;Chin et al, 2007).…”

Identification of metastasis-associated breast cancer genes using a high-resolution whole genome profiling approach

“…For determining tetraspanin 1 (TSPAN1) mRNA expression levels in human breast cancer tissues, we utilized residual RNA extracts from a prior study of primary breast carcinomas (Varma et al 2005). For determining TSPAN1 mRNA expression levels in breast cell lines, we utilized residual RNA extracts from a previously published research study that identiWed the tetraspanin NET-6 as a new breast cancer suppressor gene (Huang et al , 2007.…”

Overlay analysis of the oligonucleotide array gene expression profiles and copy number abnormalities as determined by array comparative genomic hybridization in medulloblastomas

“…These arrays consist of DNA from individual bacterial artificial chromosomes (BACs) tiled at varying intervals across the genome, where the resolution of the array is roughly proportional to the density of clones on the array. This technology has been used extensively over the past few years to study a wide variety of different cancer cell types (Brookman-Amissah et al, 2005;Nowak et al, 2005;Rossi et al, 2005;Varma et al, 2005). These aCGH studies, while more successful in identifying amplifications, have also been used to pinpoint consistent small deletions (Rossi et al, 2005).…”