Abstract 1081: Non-random genomic alterations in BRCA1-related breast cancer (2015)

Abstract BRCA1-related breast cancer is characterized by a high degree of genomic instability. However, to which extent this instability is a random result of the homologous recombination defect or the selection of the tumor phenotype, is unknown. The objective of this study is to investigate the genomic aberrations (copy number variation and somatic mutations) of BRCA1-related breast cancer, using a mouse model, to identify likely nonrandom aberrations and their biological functions. We examined genomic aberrations of three independent BRCA1-related tumors from a genetically engineered mouse model, K14-Cre BRCA1f/fp53f/f. Tumors had been propagated in Cre-negative littermates and liver tissue of the recipient mice from the controls were used as a germline control. Fresh frozen tumors and normal samples were used for exome sequencing and RNA-seq using Illumina technology. A commonly used workflow, GATK, was used for the sequence alignment, preprocessing and calling somatic mutations. VarScan2 was used for calling somatic copy number variations. We investigate the prevalence of common aberrations among these mouse in human BRCA1-related breast and ovarian cancer from The Cancer Genome Atlas (TCGA). We used the BioMart software tool to map mouse genes to human genes for the cross species analysis. After identifying common aberrant regions and genes across human and mouse we applied enrichment analysis using GOSeq, MetaCore and MSigDB software tools to identify the biological functions of the genetic alterations observed in BRCA1-related breast cancer across species. The analysis of exome sequencing data from BRCA1-related mouse tumors revealed surprisingly similar patterns of CNVs and rates of non-synonymous mutations. Correspondingly, distinct pattern were identified with regard to CNVs in human BRCA1-related breast and ovarian cancer. The cross species analysis of BRCA1-related TCGA ovarian and breast cancer tumors and BRCA1-related mouse tumors identified commonly aberrant regions that mapped to the long arms of human chromosomes 1, 8, 17 and 20 in both breast and ovarian cancer. Functionally, the blocks of genes that were commonly amplified in BRCA1-related breast or ovarian cancer included genes that transduce mitogenic signaling and ligand independent activation of estrogen receptors ESR1 and ESR2 as well as genes of the renin-angiotensin system. To conclude, copy number aberrations in BRCA1-related breast or ovarian cancers are not random and enrich for genes that enforce mitogenic signaling. The data support the notion that in addition to loss of cell cycle checkpoint control, tumor development requires activation of a mitogenic signaling program that could potentially be targeted for treatment. Citation Format: Sheida Nabavi, Kristina M. Holton, Ashish Juvekar, Nicholas Wang, Olivier Elemento, Lewis C. Cantley, Gerburg M. Wulf. Non-random genomic alterations in BRCA1-related breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1081. doi:10.1158/1538-7445.AM2015-1081