Abstract P3-04-07: Novel genetic features associated with 8p11-p12 amplification in breast carcinoma
Authors: Parris TZ , Biermann J , Engqvist H , Werner Rönnerman E , Truvé K , Nemes S , Forssell-Aronsson E , Solinas G , Kovács A , Karlsson P , Helou K 
Published: February 2018

Background: Genome instability contributes to the neoplastic phenotype by promoting gene loss and duplications, which in turn can have a detrimental effect on patient outcome by inactivating tumor suppressor genes or hyperactivating oncogenes. In breast carcinoma, DNA amplification of the 8p11-p12 genomic region has been associated with tumor progression and poor prognosis. The aim of this study was to characterize recurrent genetic features (other than DNA amplification) associated with 8p11-p12 amplification in breast carcinoma.

Methods: DNA copy number profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients diagnosed in Western Sweden between 1988 and 1999) were evaluated to identify 8p11-p12 amplified cases. Illumina paired-end whole transcriptome sequencing (RNA-seq) and whole-genome SNP genotyping were subsequently performed on 23 breast carcinomas harboring high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. The 23 samples were stratified into the molecular subtypes, resulting in 16 Luminal B/HER2-, two Luminal B/HER2+, four HER2/ER-, and one Basal-like sample. The Cancer Genome Atlas (TCGA) RNA-seq data for 10 primary breast carcinomas lacking the 8p11-p12 amplicon (SNP segmented mean &lt; 0.4) were used as controls. Gene fusions were validated using dual-color fluorescence in situ hybridization (FISH) with co-hybridized biotin-16-dUTP and dioxigenin-11-dUTP labeled bacterial artificial chromosome (BAC) probes.

Results: Here, we report that despite the high number of gene fusions (133±31 (±SEM)) and exonic variants (411±16) identified per tumor, few gene fusions (n=46) and exonic variants (n=11) spanned the 8p11-p12 genomic region. Gene fusions predominantly contained at least one fusion partner spanning non-coding RNAs (ncRNAs; 86%), in particular MALAT1, which is induced by estrogen and of prognostic value in breast cancer. The majority of fusion breakpoints were associated with DNA copy number gains and losses, as well as, extensive intratumoral heterogeneity for specific fusion events. Intriguingly, novel 8p11-p12 amplification-specific genetic variants (HIST1H1E frameshift insertion, UQCRHL nonsynonymous SNV, MTUS1 frameshift insertion, NPIPA5 frameshift deletion) were identified that also resulted in mutation-dependent changes in gene expression levels.

Conclusions: Taken together, these findings have provided further insight into the genetic landscape of 8p11-p12 amplified breast carcinomas, including novel gene fusions and genetic variants. However, further studies are required to develop effective strategies to target 8p11-p12 amplification in breast carcinoma.

Citation Format: Parris TZ, Biermann J, Engqvist H, Werner Rönnerman E, Truvé K, Nemes S, Forssell-Aronsson E, Solinas G, Kovács A, Karlsson P, Helou K. Novel genetic features associated with 8p11-p12 amplification in breast carcinoma [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-07.