Identification by array comparative genomic hybridization of a new amplicon on chromosome 17q highly recurrent in BRCA1 mutated triple negative breast cancer

Abstract

IntroductionTriple Negative Breast Cancers (TNBC) represent about 12% to 20% of all breast cancers (BC) and have a worse outcome compared to other BC subtypes. TNBC often show a deficiency in DNA double-strand break repair mechanisms. This is generally related to the inactivation of a repair enzymatic complex involving BRCA1 caused either by genetic mutations, epigenetic modifications or by post-transcriptional regulations.The identification of new molecular biomarkers that would allow the rapid identification of BC presenting a BRCA1 deficiency could be useful to select patients who could benefit from PARP inhibitors, alkylating agents or platinum-based chemotherapy.MethodsGenomic DNA from 131 formalin-fixed paraffin-embedded (FFPE) tumors (luminal A and B, HER2+ and triple negative BC) with known BRCA1 mutation status or unscreened for BRCA1 mutation were analysed by array Comparative Genomic Hybridization (array CGH). One highly significant and recurrent gain in the 17q25.3 genomic region was analysed by fluorescent in situ hybridization (FISH). Expression of the genes of the 17q25.3 amplicon was studied using customized Taqman low density arrays and single Taqman assays (Applied Biosystems).ResultsWe identified by array CGH and confirmed by FISH a gain in the 17q25.3 genomic region in 90% of the BRCA1 mutated tumors. This chromosomal gain was present in only 28.6% of the BRCA1 non-mutated TNBC, 26.7% of the unscreened TNBC, 13.6% of the luminal B, 19.0% of the HER2+ and 0% of the luminal A breast cancers. The 17q25.3 gain was also detected in 50% of the TNBC with BRCA1 promoter methylation. Interestingly, BRCA1 promoter methylation was never detected in BRCA1 mutated BC. Gene expression analyses of the 17q25.3 sub-region showed a significant over-expression of 17 genes in BRCA1 mutated TNBC (n = 15) as compared to the BRCA1 non mutated TNBC (n = 13).ConclusionsIn this study, we have identified by array CGH and confirmed by FISH a recurrent gain in 17q25.3 significantly associated to BRCA1 mutated TNBC. Up-regulated genes in the 17q25.3 amplicon might represent potential therapeutic targets and warrant further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0466-y) contains supplementary material, which is available to authorized users.

A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy

“…UBE2O is localized in the 17q25 locus, the amplification of which is recurrent in a subset of human cancers (Briffa et al, 2015; Lin et al, 2006; Rice et al, 2011; Toffoli et al, 2014; Wang et al, 2015), and we found that in TCGA datasets from cBioPortal (www.cbioportal.org) UBE2O is upregulated in ~20% of human breast, bladder, liver and lung carcinomas (Figures 7A and 7B and Figures S7A and S7B). Previously published microarray-based gene expression analyses have also indicated a high expression rate of UBE2O in several subsets of human cancer (Figure 7C and Figure S7C).…”

“…However, in vivo evaluation of UBE2O has been limited by a lack of appropriate animal models. Intriguingly, UBE2O is localized in the 17q25 chromosome region, which is amplified in a subset of human cancers (Briffa et al, 2015; Lin et al, 2006; Rice et al, 2011; Toffoli et al, 2014; Wang et al, 2015), but its role in tumorigenesis has yet to be fully described.…”

Basal-like breast cancer: molecular profiles, clinical features and survival outcomes

“…For instance, amplifications in 8q21 have been associated with high tumour grade, high levels of Ki67 and other proliferation markers, including MYC , MDM2 and CCND1 [99]. Gains in 10p have further differentiated triple-negative cancers [48], and in 17q25 have distinguished BRCA1 -mutated tumours [100]. …”

Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry

“…Using SNPs might potentially be better able to improve risk prediction models than using other risk factors for breast cancer (2). For example, perhaps because of the correlation between the mammographic density risk factor and the risk factors involved in the BCRAT model, the inclusion of mammographic density resulted in only a modest improvement in AUC for BCRAT (34, 35).…”